RFA-RM-08-005: Molecular Libraries Probe Production Centers Network (MLPCN) (U54)

Part I Overview Information

Department of Health and Human Services

Issuing Organization
National Institutes of Health (NIH), (http://www.nih.gov)

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
This RFA is developed as an NIH Roadmap initiative (http://nihroadmap.nih.gov ). All NIH Institutes and Centers participate in roadmap initiatives. The RFA will be administered by the National Institute of Mental Health and the National Human Genome Research Institute on behalf of the NIH. http://www.nimh.nih.gov, http://www.nhgri.nih.gov

Title: Molecular Libraries Probe Production Centers Network (MLPCN) (U54) – Limited Competition

Announcement Type
New

Request For Applications (RFA) Number: RFA-RM-08-005

Catalog of Federal Domestic Assistance Number(s)
93.310

Key Dates
Release Date: November 9, 2007
Letters of Intent Receipt Date: December 13, 2007
Application Receipt Date: January 10, 2008
Peer Review Date: March 2008
Council Review Date: May 2008
Earliest Anticipated Start Date: July 1, 2008
Additional Information To Be Available Date (Url Activation Date): Not Applicable
Expiration Date: January 11, 2008

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Purpose. This Funding Opportunity Announcement (FOA) will establish a network of screening and probe generation centers that will use high-throughput screening and chemistry to discover small molecules that can be used as new molecular tools to aid the investigation of protein function, signaling pathways and cellular processes that are important to the maintenance of human health and to accelerate the development of new therapeutics. This NIH Roadmap RFA is a limited competition restricted to those applicants to PAR-07-368 (X02) who after review have been invited to submit full U54 applications.
The announcement solicits applications for three types of screening and chemical probe generation centers with complementary capabilities to comprise a research network that will have a high degree of flexibility to address a wide range of biological targets and phenotypes in the production phase of the Molecular Libraries Program (MLP). Applicants may request that a portion of the funds be used for one or more creative, highly innovative research projects whose aim is to advance state of the art in probe generation and thereby enhance the achievement of the overall objectives of the network to deliver advanced research tools and knowledge to the scientific community and to stimulate the adoption of chemical genomics as a new discipline in biomedical research.
The goal of the MLP is to screen compounds in the Small Molecule Repository in biochemical, cell-based and possibly model organism assays, and to identify and subsequently optimize small molecules as research probes. All assay information and data from the MLP will be rapidly made available in PubChem for the research community to use in exploring the function of major components of the cell in health and disease. Applicants may submit an application for a Comprehensive Center, a Specialized Screening Center, or a Specialized Chemistry Center.
The program is a follow on to the Molecular Libraries Screening Centers Network (MLSCN) (http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-017.html).
Mechanism of Support. This RFA will utilize the NIH Specialized Centers Cooperative Agreement funding mechanism (U54).
Funds Available. The total funds available from the NIH Roadmap for the new awards are approximately $70 million per year for the four-year production phase.
Budget and Project Period. This FOA is for a funding period of six years; for years 1-4, full funding will be provided by the NIH Common Fund. Years 5 and 6 will transition the MLPCN from the NIH Common Fund support to other sources of support. The MLP anticipates awarding up to 2-4 Comprehensive Centers, 2-3 Specialized Screening Centers, and 2-3 Specialized Chemistry Centers. Comprehensive Center applicants may request up to $10 million direct costs annually; Specialized Screening Center applicants may request up to $2.1 million direct costs annually; Specialized Chemistry Center applicants may request up to $2.85M direct costs annually.
Institutions/Organizations. Public/State Controlled Institution of Higher Education; Private Institution of Higher Education; Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education); Nonprofit without 501(c)(3) IRS Status (Other than Institution of Higher Education); For-Profit Organization (Other than Small Business); State Government; U.S. Territory or Possession; Domestic Institutions and eligible agencies of the U.S. Government.
Project Directors/Principal Investigators (PDs/PIs). Eligible project directors/principal investigators(PD/PIs) include individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
Number of Applications. An individual can serve as a PD/PI on only one application. There are no limits on the number of applications that can be submitted by one organization.
See Section IV.1 for application materials.
Telecommunications for the hearing impaired are available at: TTY 301-451-0088
Special Receipt Date January 10, 2008

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
  1. Research Objectives

Section II. Award Information
  1. Mechanism(s) of Support
  2. Funds Available

Section III. Eligibility Information
  1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
  2.Cost Sharing or Matching
  3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
  1. Address to Request Application Information
  2. Content and Form of Application Submission
  3. Submission Dates and Times
    A. Receipt and Review and Anticipated Start Dates
      1. Letter of Intent
    B. Sending an Application to the NIH
    C. Application Processing
  4. Intergovernmental Review
  5. Funding Restrictions
  6. Other Submission Requirements

Section V. Application Review Information
  1. Criteria
  2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Sharing Research Data
    D. Sharing Research Resources
  3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
  1. Award Notices
  2. Administrative and National Policy Requirements
    A. Cooperative Agreement Terms and Conditions of Award
      1. Principal Investigator Rights and Responsibilities
      2. NIH Responsibilities
      3. Collaborative Responsibilities
      4. Arbitration Process
  3. Reporting

Section VII. Agency Contact(s)
  1. Scientific/Research Contact(s)
  2. Peer Review Contact(s)
  3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

A. Background:

The NIH Roadmap is a series of trans-NIH research programs designed to foster new ways of doing research, to fill fundamental knowledge gaps, and to encourage risk taking to solve complex problems. The overarching criterion for Roadmap programs is that they are expected to transform the way research is conducted across the spectrum of health research (http://nihroadmap.nih.gov/ ). The Molecular Libraries and Imaging Initiative (MLI) is one of the components currently comprising the Roadmap theme of ‘New Pathways to Discovery,’ the goal of which is to build better tools to use in studying the many interconnected networks of molecules that comprise cells and tissues, their interactions, regulation, and the combination of molecular events that lead to disease. In the initial pilot phase, the primary objective of the Molecular Libraries Initiative was to introduce chemical genomics as a major new approach for public sector research. In the production phase, the MLI will become the Molecular Libraries Program (MLP) with a focus on probe discovery and development.

A1. Molecular Libraries Program: Pilot Phase. The MLI was begun in FY 2004 to pilot a set of components aimed at developing selective and potent chemical probes for use in basic research. The three main components were data production, data dissemination, and technology development. Data production in the pilot phase involved: (a) the Molecular Libraries Small Molecule Repository (MLSMR) to establish and provide access to a unique and diverse library of compounds; (b) support of assay implementation through the Solicitation of Assays for High Throughput Screening (HTS) in the Molecular Libraries Screening Centers Network initiatives, PAR-06-545 (R03) and PAR-06-259 (X01), and the Guide Notice NOT-RM-07-012 announcing Fast Track entry to the MLSCN; and (c) the Molecular Libraries Screening Center Network (MLSCN) to implement assays provided by the wider research community and generate chemical probes for the scientific community. Data dissemination was supported by PubChem, the primary portal through which the screening and chemistry results of the MLSCN are made public. Technology development supported advances in a number of aspects of the probe generation process, including: (a) Chemical Diversity development with the Pilot–Scale Libraries (PSL) for High-Throughput Screening (RFA-RM-06-003 (P41)) a program to support the development of pilot-scale chemical diversity libraries for screening in the MLSCN and New Methodologies for Natural Products Chemistry (RFA-RM-05-013 (R01)) a program to develop new methods for natural products chemistry; (b) Assay Development for High Throughput Screening (RFA-RM-07-008 (R21)) a program to support the development of novel bioassays that have the potential to advance scientific discovery, emphasizing assay novelty and the current availability of probes; (c) Molecular Libraries Screening Instrumentation (RFA-RM-04-020 (R01)) a program to support the development of breakthrough instrumentation technologies; (d) the Exploratory Centers for Cheminformatics Research (ECCRs) (RFA-RM-05-012 (P20)) with multiple roles including high-level data analysis and dissemination with a focus on developing new understanding of cellular processes (genes and pathways); (e) Novel Preclinical Tools for Predictive ADME/Toxicology (RFA-RM-04-023 (R21)); (f) Molecular Imaging and Contrast Agent Database (MICAD) which contained imaging probe information; (g) High-Specificity/High-Sensitivity Molecular Imaging Probes (RFA-GM-08-009 (R01)), RFA-GM-07-234 (R01)) program to develop imaging agents for basic or clinical applications with an emphasis on enhancing the specificity and resolution of the agents by an order of magnitude and (h) the Imaging Probe Development Center (IPDC) an NIH intramural center effort that offers the production of known imaging probes for the research community. The expired FOAs for these components can be found at https://mli.nih.gov/mlscn/index.php .

In the pilot phase, the MLSCN comprised a network of nine extramural and one NIH intramural screening centers. Each screening center has implemented innovative HTS approaches to identify compounds that are active in biochemical, cell-based or model organism assays using multiple screening formats including target-based, reporter and phenotypic screens. To date, the MLSMR has acquired and maintains a unique and diverse collection of nearly 200,000 compounds obtained from both commercial and academic sources as a screening library for the MLSCN. Active compounds identified through initial screening of the library are further developed within the MLSCN through a combination of structure-activity analysis and synthetic chemistry to obtain useful bioactive probes. The centers have adopted an eleven-step process to provide consistent, high quality data on compound structures, screening data, and assay protocols to the public through the PubChem database (see chemical probe development path, https://mli.nih.gov/resources/MLPCN_U54_FAQ.htm). Information in PubChem is available to all researchers for use in biological and biomedical research studies (http://pubchem.ncbi.nlm.nih.gov/ ).

B. Molecular Libraries Program: Production Phase.

With the end of the MLI pilot phase, this FOA solicits applications that will implement the transition of the MLP to a full-scale production phase where the program emphasis will be on the generation of high quality probes and biological-chemical data for high-value targets. It is expected that all applicants will be at full production rate defined in this FOA for each type of center no later than the end of the first grant year.

B1. Program Objectives. The long-term goal of the MLP is to develop new small molecule probes that will be used as research tools in the identification and analysis of protein function, signaling and metabolic pathways and cellular function important to the maintenance of human health, with the expectation that increased knowledge and wider understanding of probe chemistry will accelerate the development of new therapeutics. The major programmatic goal is to establish a valuable community resource/repository of compounds, probes and biochemical data for furthering research to benefit the public health. As a central component of the MLP, the MLPCN program will continue to offer HTS resources to the scientific community under its Data Sharing and Intellectual Property (IP) policies (see NIH Policy on Data Sharing and IP in the MLP, http://www.nimh.nih.gov/about/organization/dnbbs/the-mlscn-project-team-policy-on-data-sharing-and-ip-in-the-mlscn-program.pdf). These policies are designed to speed the dissemination of screening results and new molecular research tools (e.g., ligands, imaging probes, and new activities of existing drugs) to the public sector for their immediate use. The MLP also intends to stimulate research in the following areas: 1) discovery of novel probes directed against biological targets that can inform studies of cell function and disease mechanisms; 2) development, validation, and application of screening assays and disease models to evaluate the activities of novel small molecules; and 3) use of chemical genomic approaches to characterize the biology of genes of interest, cellular processes, and proteins associated with disease processes.

The NIH anticipates that the MLPCN will have sufficient capacity to screen the MLSMR library (a minimum of 300,000 and as many as 500,000 compounds as the library expands in size) each year in 100 assays that have been adapted for automated screening. Thus, the specific goal of this FOA is to announce a limited competition that is the second phase of the solicitation process that began with PAR-07-368 (X02). Invited applicants may submit applications to participate in the production phase of the MLP that, overall, will have the capabilities to: 1) implement a diverse array of both target-based, and phenotypic assays obtained from investigators in the public or private sector; 2) screen a large number of compounds that comprise the screening collection in the MLSMR for biological activity in these assays; 3) employ medicinal chemistry (synthetic and computational) to optimize screening hits into useful in vitro and/or in vivo biological probes; and 4) provide informatics support to track compounds, assays, screening and chemistry data. The MLPCN will make all biological screening data, assay and text descriptions of reaction protocols, and structures of chemical probes and related chemical data such as structure-activity relationships (SAR) freely available to the public through the PubChem database.

B2. Core Capabilities of the MLPCN. The MLPCN will be established as a collaborative research network of Comprehensive Centers and Specialized Screening and Chemistry Centers with complementary abilities that will enable screening of diverse types of assays and generation of chemical probes to address a wide range of biological opportunities. It is envisioned that each center will bring to the network a specific set of expertise and skills in the main functions/cores appropriate to the type of center (i.e., assay development, assay adaptation/implementation, HTS, informatics, (SAR)/cheminformatics and chemistry); see link for definition of terms, https://mli.nih.gov/resources/MLPCN_U54_FAQ.htm. It is also envisioned that the organization of the centers into a functioning network will allow the MLPCN to achieve synergies and thereby (1) advance the state of the art in chemical genomics more rapidly than if the same centers functioned in isolation and (2) effect the uptake of chemical genomics by the wider scientific community as a new approach that will enable the biomedical research enterprise to provide scientific validation of critical drug targets and accelerate development of new therapeutics to improve the health of the public.

One of the primary goals of the MLPCN is the production of new and useful chemical probes for biomedical research. The minimum characteristics that a probe compound will need to have to be a useful research tool has been determined by the MLPCN Steering Committee and the MLP Project Team. According to the definition currently used by the MLSCN, these characteristics include <100 nM affinity, >10-fold selectivity against related targets, and solubility in aqueous solutions (possibly including a low concentration of DMSO). Most importantly, a chemical probe must represent an improvement over existing probes for the designated target (https://mli.nih.gov/resources/MLPCN_U54_FAQ.htm). NIH recognizes that whatever the characteristics of the probes, further modification may be necessary to produce compounds that are useful for in vivo studies. However, such additional efforts are outside of the activities called for in this FOA. It is the desire of NIH that during the production phase, all probes and all related biological and chemical data will be made available to all researchers.

B3. Program Changes for the Production Phase. The production phase of the Molecular Libraries Probe Production Center Network (MLPCN) will differ from the pilot phase (MLSCN) in several strategic ways based on knowledge and on experience gained during the pilot phase.

In contrast to the ten similarly structured centers of the pilot phase, the MLPCN will be composed of three different types of centers working together as a network to provide improved handling of the diverse classes of investigator-submitted assays as well as enhanced chemistry support for the large number of active compounds identified by the screening centers;
With the advent of Specialized Chemistry Centers expanding program chemistry resources, there is an increased emphasis on network communication and interaction;
In addition to providing a probe development resource for investigator submitted assays as a service to the community, each Center will have the option of initiating center-defined research in support of MLP goals;
Each screening center will be expected to have an assay development/assay implementation function to permit development of investigator submitted assays that require minor modification before screening;
The first step for all centers is the creation of a Compound Probe Development Plan (CPDP) by the project team composed of center staff, the assay provider and a NIH Network Science Officer assigned to the assay project. The CPDP outlines the projected probe development path for the specific assay, assigns tasks to each member of the project team and predicts appropriate milestones and timelines.
Each screening center will be expected to provide an active outreach program to increase interest of the biomedical community in submitting assays to the MLPCN and provide support to aid an assay submitter in preparing a competitive X01 or R03 Assay Solicitation application.
Each screening center should provide support to assay providers for scaling up production of reagents necessary for performing HTS and secondary assays;
Each screening center should expect to run the primary and all secondary screening assays, including one or more alternative screens, as defined in the Chemical Probe Development Plan (CPDP), please see definition of terms at https://mli.nih.gov/resources/MLPCN_U54_FAQ.htm.

C. Types of MLPCN Centers.

The three types of centers for which applications are being solicited are: Comprehensive Centers each with the capability to screen 300,000-500,000 compounds against at least 20-25 assays per year and provide SAR analysis and medicinal chemistry to identify potent and selective chemical probes; Specialized Screening Centers each with the expertise and experience to successfully implement complex and technically difficult assays that may not be amenable to HTS (e.g., high content screening, phenotypic assays, ion channel screening, whole organism screening); and Specialized Chemistry Centers each with outstanding capabilities in applying medicinal chemistry in order to advance early hits to chemical probe status. As an integral part of the network, the Specialized Chemistry Centers will actively participate with both types of screening centers to generate probes. Further details on the integration of the probe pipeline, center cores and the overlapping roles of the comprehensive and specialized centers can be seen under “Center Infrastructure” at https://mli.nih.gov/resources/MLPCN_U54_FAQ.htm).

C1. Comprehensive Centers. The Comprehensive Centers will provide rapid screening of a broad diversity of assays (e.g. enzymes/proteases, G-protein coupled receptors, kinases, cytotoxicity, protein-protein interactions, protein misfolding/degradation, high-content screening, transcription/expression, etc) using a number of detection platforms. These large, ultrahigh-throughput screening centers will contain all the necessary functions to take a project through the complete chemical probe development process from creation of a Chemical Probe Development Plan and assay development to chemical synthesis of potent and selective probe compounds. The key functionalities or cores required by these centers are: assay development, assay adaptation/implementation, HTS, informatics, SAR/cheminformatics and chemistry. All centers will be expected to apply process management methods of planning, monitoring and evaluating of process performance as part of their management of their portfolio of assays and probe development projects over the lifetime of the grant period. Each Comprehensive Center will be expected to define a set of specific center milestones, including production rate, program efficiency and costs; these will be useful management tools for the PI as well as allow careful monitoring by NIH program staff. Each center is expected to be able to screen a library of 300,000-500,000 compounds per assay, process 20-25 or more assays per year, and undertake 20-25 or more probe projects per year in order to deliver 10-15 new probes per year once the discovery pipeline is at full capacity. To be competitive for funding under this FOA, the application must demonstrate that the proposed center can achieve this production capacity at the time the award is made or no later than the end of the first year of funding. Each center also will be required to develop an active outreach program to (1) increase awareness of the biomedical community in the goals of the MLP and more generally, the value of chemical genomics to biomedical research, (2) to solicit investigators to submit assays to the MLPCN and (3) to provide support to aid assay submitters in preparing a competitive X01 or R03 Assay Solicitation application. A Comprehensive Center will be responsible for all three of the following operational stages in the probe generation pipeline:

a. Hit identification: The identification of hits will require the centers to have the capability for assay development, assay adaptation/implementation, HTS and informatics to accept assays into the center, modify and implement them for automated HTS; for screening the MLSMR library of compounds; and for confirming initial hits by re-screening. The first step in implementing an assay is the creation of a Compound Probe Development Plan (CPDP) by the project team composed of center staff, the assay provider and a NIH Network Science Officer assigned to the assay project. The CPDP outlines the projected probe development path for the specific assay, assigns tasks to each member of the project team and predicts appropriate milestones and timelines (see link for example of a CPDP (https://mli.nih.gov/resources/MLPCN_U54_FAQ.htm). Applicants should describe how they will incorporate the CPDP into their hit identification process.

b. Hit characterization: Fresh compound samples of initial hits will be selected (cherry-picked) by the MLSMR and sent to the centers for further characterization. Working with the assay provider, valid hits should be characterized in an alternative assay to that used in the primary screen. This provides additional verification that the hit is acting on the target of interest. Depending on the assay and target, the assay implementation and HTS cores may choose to develop counter-screens to determine the selectivity and specificity of the hits for the target. All secondary screens (alternative, concentration–dependent and counter screens) will be the responsibility of the screening center. The informatics and chemistry cores will analyze the data for correlations between compound structure and the observed biological activity (SAR analysis). All assay data on hit characterization will be promptly deposited into PubChem.

c. Hit to probe optimization: To optimize initial hits, the assay implementation, informatics and chemistry cores will work together with the assay provider through successive rounds of synthesis and testing of new compounds to improve the potency and selectivity of the original hits. New compounds for testing in this phase often begin with the purchase of analogs structurally related to the hit, if they are available. In many instances, a compound may not be found by purchase that meets the probe criteria defined in the CPDP. In those instances, the center will need to provide sufficient synthetic chemistry to generate a library of structurally related analogs to identify compounds of improved affinity, specificity and solubility. The center should expect to continue hit optimization until a compound is identified with the appropriate properties of a probe or determine by analysis that the structure series under investigation will be unproductive. This may involve testing anywhere from <20 to a few hundred analogs; the application should describe the center’s process for making a “go/no go” decision for further chemistry activities. If confirmed hits are flagged as compounds provided by compound contributors to the MLSMR, the contributors may be invited to consult with the project team. If the project team decides on starting a chemistry campaign, the contributor may be asked as part of the project team to provide medicinal chemistry support in the development of a probe. Each center may expect to undertake 25 or more probe projects per year and deliver 10-15 new probes per year once the discovery pipeline is at full capacity.

C2. Specialized Screening Centers: Certain types of assays requiring multiple steps or specialized instrumentation (e.g. phenotypic imaging assays, multiplexed flow cytometry, ion channel assays) may not fit well in the comprehensive center format due to their special requirements and slower screening rates. However, these more difficult assays for screening large compound sets may represent the only technology available for newly discovered targets and pathways. Assays of this type are windows to important biological phenomena and are, accordingly, an important objective of the MLP. To address these needs and opportunities, the MLP has introduced the concept of Specialized Screening Centers in the production phase. The Specialized Screening Centers will be smaller in scope, but similarly expected to apply novelty and innovation to specific types of assays or platforms. These centers will need to have assay development, assay adaptation/implementation, screening and informatics functional cores. Each center is expected to try to screen a library of 300,000-500,000 compounds per primary assay and process 5 or more assigned assay projects per year. NIH understands, however, that some assays might not be amenable to screening with such a large screening library, and therefore will be willing to consider approving use of subsets of the library on a case by case basis. If the applicant anticipates that this may be an issue, s/he should describe how such a problem would be identified and the approach that would be taken to determine an appropriate screening set recognizing the importance NIH places on the development of biological profiles for each compound in the MLSMR that derive from screening of the complete library and deposition of the screening data in PubChem. In collaboration with a Specialized Chemistry Center or the chemistry core of a Comprehensive Center that can provide cheminformatics and chemistry resources, the Specialized Screening Center is expected to deliver 2-3 new probes per year once the discovery pipeline is at full capacity. Each center is encouraged to develop an active outreach program to (1) increase awareness in the biomedical community of the goals of the MLP, (2) to solicit investigators to submit assays to the MLPCN and (3) to provide support to aid the assay submitter in preparing a competitive X01 or R03 Assay Solicitation application. A Specialized Screening Center will be responsible for “Hit identification”, “Hit characterization” and, in collaboration with a Specialized Chemistry Center or the chemistry core of a Comprehensive Center, “Hit to probe optimization” stages in the probe generation pipeline. All centers will be expected to apply process management methods of planning, monitoring and evaluating process performance as part of their management of their portfolio of assays and probe development projects over the lifetime of the grant period. Specific center metrics including production rate, program efficiency and costs will be carefully monitored by NIH program staff.

a. Hit identification: The Specialized Screening Centers will run a primary screen, perform confirmatory assays and analyze all the data before deposition into PubChem. The throughput of many of these assays will be relatively low because the emphasis of the Specialized Center’s component of the MLPCN is not screening rate but the opportunity to include other medium and low throughput screening methods for difficult assays or assays not amenable to present HTS methods (i.e., inaccessible targets or complex phenotypes). Complete screening of the MLSMR library is expected, but this will be anticipated to occur over a longer time span than an assay campaign in the Comprehensive Centers. Applicant’s will need to provide information on the center’s capability for assay development, assay adaptation/implementation, HTS and informatics functional cores and describe how the center will accept, modify and implement assays for automated HTS, screen the MLSMR library and confirm initial hits. Explain how the project team will be formed for each assigned assay project and how the CPDP will be created and used to guide the probe development process.

b. Hit characterization: Immediately following completion of the primary screen, fresh compound samples of initial hits (cherry-picked) will be provided by the MLSMR for hit confirmation and secondary screens. Working with the assay provider, valid hits will need to be characterized in an alternative assay to verify that the compound is target specific. Depending on the assay and target, the center will develop counter-screens to determine the selectivity and specificity of the hits for the target. All secondary screens (alternative, concentration–dependent and counter screens) will be the responsibility of the screening center.

c. Hit to probe optimization: At an early stage in hit characterization, the Specialized Screening Center will identify within the MLPCN a Specialized Chemistry Center or the chemistry core of a Comprehensive Center capable of providing chemistry resources (both synthetic and cheminformatics) for hit-to-probe optimization. In this collaborative effort, the Specialized Screening Center will provide all follow-up assays on the compound analogs. To optimize initial hits, the biologists, chemists and cheminformaticians will work together with the assay provider through successive rounds of synthesis and testing of new compounds to improve the potency and selectivity of the original hits. New compounds for testing in this phase should begin with the purchase of analogs structurally related to the hit, if they are available. If a probe cannot be found by compound purchase that meets the probe criteria defined in the CPDP, the center providing chemistry resources will generate a library of structurally related analogs to identify compounds of improved affinity, specificity and solubility. Before synthesis is attempted, the participating MLPCN centers working with the NIH Network Science Officer and the assay provider will update the CPDP to clearly identify all relevant go/no-go criteria and appropriate milestones and timelines. If confirmed hits are flagged as compounds provided by compound contributors to the MLSMR, the contributors may be invited to consult with the project team. If the project team decides on starting a chemistry campaign, the contributor may be asked as part of the project team to provide medicinal chemistry support in the development of a probe.

C3. Specialized Chemistry Centers: The “hit-to-probe” optimization stage in the probe development process may require special tools, expertise, and resources that are frequently in short supply in a screening center. Specialized Chemistry Centers will apply innovative and novel approaches of cheminformatics and medicinal chemistry to advance active compounds identified by the Specialized Screening Centers or, in some instances, by the Comprehensive Centers. It is essential that compounds identified as research tools for the investigation of particular targets and biological processes by the MLPCN are reliable and capable of providing valid information on the activity of their intended targets. The probe compounds produced by the centers will need to be usable by the research community for in vitro and/or in vivo studies. In most cases, compounds identified by initial screening (“hits”) will not be ideal as research tools. It is likely that properties such as affinity, specificity, and solubility will need to be improved using the chemistry resources of the Specialized Chemistry Center. Specific center metrics including production rate, program efficiency and costs will be carefully monitored by NIH program staff.

a. Hit to probe optimization: Probe leads identified from screens in the Screening Centers will require further optimization through chemistry. A joint effort will begin during the hit characterization stage by formation of a project team that includes the screening center, the chemistry center, the assay provider and the NIH Network Science Officer for hit-to-probe optimization. This joint effort will match the rich chemistry resources of the Specialized Chemistry Center with the counter-screen and follow-up screens of the Screening Center in a close collaboration. New compounds for testing in this phase usually are obtained first by purchase of analogs structurally related to the hit before considering the more expensive approach of synthesis of new analogs. If a probe can not be found by compound purchase that meets the probe criteria defined in the CPDP, the Chemistry Center will provide sufficient synthetic chemistry to generate a library of structurally related analogs to identify compounds of improved affinity, specificity and solubility. The center should be expected to continue hit optimization until a compound is identified with the properties defined in the CPDP. Before synthesis is attempted, the project team will update the CPDP to clearly identify all relevant go/no-go criteria and appropriate milestones and timelines. In this collaborative effort, the screening center will provide all follow-up assays on the compound analogs. If confirmed hits are flagged as compounds provided by compound contributors to the MLSMR, the contributors may be invited to consult with the project team. If the project team decides on starting a chemistry campaign, the contributor may be asked as part of the project team to provide medicinal chemistry support in the development of a probe. Each Specialized Chemistry Center can expect to undertake 10 or more probe projects per year from the combined hits from both Specialized Screening Centers and Comprehensive Centers and deliver 4-6 new probes per year once the discovery pipeline is at full capacity.

Note: Because the goal of screening 300,000 compounds in 100 assays annually may be an under- or over-estimate, this goal will be re-assessed by the MLPCN, the External Scientific Panel (ESP), and the MLP Project Team at the Mid-course Review.

D. Center-driven research projects.

The MLP is included in the NIH Roadmap because of its potential to transform the way in which biomedical research is done by introducing the capacity for high-throughput probe development into public sector research and advancing the potential offered by chemical genomics. As the focus of the MLP, the MLPCN centers can contribute not only through the process of screening individual investigator-submitted assays. By virtue of their insight into the-probe development process, the centers have the opportunity to explore and develop truly revolutionary advances that a more comprehensive approach to chemical genomics could provide. To stimulate potentially high impact advances in chemical genomics, NIH will offer to applicants the opportunity to include research component in the center applications. NIH invites applicants to include proposals for highly creative, innovative research projects that could make major contributions to 1) the advancement of chemical genomics as an important new discipline for public sector research that is widely available to the academic research community, and 2) enhancement of the ability of public sector researchers to regularly use small molecules as investigative tools. Applicants may request support for up to 6 years for research based on a well articulated vision advancing the use of small molecules by the academic biomedical research community for the investigation of important unmet challenges. The proposal for this “center-driven” program should describe a broad vision of the current state of the art, identify the opportunities that new capabilities in chemical genomics offers, and describe a research program that would lead to high impact advances in biology and biomedicine. The research proposal must clearly identify a set of specific aims that would lead to the realization of the vision and a project or series of projects by which those aims would be achieved. For example, applicants could identify one or more major restriction(s) or bottleneck(s) in the high-throughput technologies for chemical genomics, in the design and synthesis of new small molecules based on initial hits, or in application of chemical genomics to important biomedical research problems and then describe one or more inventive research projects that would address the bottleneck and provide high impact, broadly enabling advances in the development of methods and tools to study the protein networks and cellular processes important in the molecular events that lead to disease. These aims can include projects that are biologically, chemically or computationally driven either alone or in an integrated fashion.

In developing their plans for the center-driven component, applicants are advised to propose high impact/high payoff projects that leverage the unique strength(s) of their proposed center. Up to 30% of the maximal allowed budget per year may be requested for the center-driven research project(s). To provide the MLP with the maximum flexibility to pursue exciting new directions offered through progress of these center-driven efforts, the center-driven programs will be evaluated at specific times during the project period, and the outcome of this assessment may result in changes in the level of funding (see Section IIF2, Requirements for Center-driven Research Project). The evaluation will be conducted by NIH staff with the assistance of outside experts and members of the External Scientific Panel. The evaluation will be based on effort, scientific progress and continued relevance of the project(s) to the articulated vision and specified aims.

The center awardees' yearly milestones for the user-driven and center-driven components will be provided to the Project Scientists(s), the MLP Project Team, the MLIIG Working Group, and the ESP. It is expected that the milestones will be adjusted annually at the award anniversary dates, both to incorporate the group's scientific accomplishments and progress, as well as to reflect any recommendations of the MLP Project Team and the ESP. Following the review of milestones, the MLP Project Team may recommend reducing or withholding funds for any center/center project that substantially fails to meet its milestones or, if the situation warrants, augmenting any center/center project. However, simply meeting milestones may not be considered sufficient accomplishment for maintaining funding at the initially committed level for the user-driven and center-driven components. Failure to remain at state-of-the-art will also be considered grounds for reduction in funding levels.

E. Organizational Structure of the MLPCN

Applications for the three types of centers will need to address two separate program components: 1) the core capabilities appropriate to the specific type of center defined as the “user-driven component” (designated as F1a-d below) and 2) the center-driven research project. These components require separate sets of specific aims, milestones, timelines and detailed descriptions of quantitative measures for monitoring progress.

The user-driven component is required and describes the service oriented function of the center to provide identification and development of probes and probe generation data. The applicant may request up to 70% of the maximal allowed budget be dedicated to the service function for assays submitted by the scientific community through the assay development and the HTS-ready assay solicitation sub-initiatives of the MLP. Assays for this component will also come from the center’s own outreach efforts that will include expert assistance to outside investigators in the development of their assays. The majority of funds for this component must be committed to providing service and not to center development.

The center-driven component allows the applicant to propose a 6 year plan that may be comprised of one or more projects that will advance the overall objectives of the network and contribute to maintaining a current and competitive network environment to deliver state of the art tools and knowledge to benefit the scientific community. Applicants may request that up to 30% of the maximal allowed budget be dedicated to this center-defined research component to pursue creative, highly innovative research project(s) whose aim is to advance the overall objectives of the network and contribute to maintaining a current and competitive network environment to enhance its mission to deliver state of the art tools and knowledge to the scientific community. The requested budget for the center-driven component cannot exceed 30% of the allowable budget for each type of center.

F. Center Core Capabilities:

F1a. Assay Development and Adaptation (applicable to Comprehensive and Specialized Screening Centers). The goal of the MLPCN is to establish innovative biochemical, biophysical, and cell-based assays for biological targets or processes for which no highly specific and potent small molecule activator or inhibitor is broadly available. However, the initial design and development of assays is not within the scope of this FOA and will not be the responsibility of the MLPCN centers. Rather, investigators in the broader scientific community will submit applications in response to NIH Guide program assay solicitation announcements (e.g., PAR-08-006 R03, and PAR-08-007 X01). These assay applications will be evaluated through a competitive process as described below. The MLPCN centers will then be responsible for importing, adapting and optimizing specific assays selected for implementation within the MLPCN. The first step in implementing an assay is the creation of a CPDP by a project team composed of center staff, the assay provider and an NIH Network Science Officer assigned to the assay project. The CPDP outlines the projected probe development path for the specific assay. The plan assigns tasks to each member of the project team and predicts appropriate milestones and timelines. Importantly, the CPDP defines the specific criteria that a compound must meet to be considered a probe for the project. During the hit characterization stage (or earlier) the CPDP should be updated to include SAR around chemotype/structural series along with a synthetic plan.

The proposed goal of the production center network will initially be to screen the MLSMR library of 300,000 compounds in 100 or more assays in the first year of the MLPCN program using 96-well, 384-well or 1536-well plates, with an expected goal of screening up to 500,000 compounds as the MLSMR expands in a minimum of 100 assays by the third year of the production phase. Although the majority of assays will be HTS-ready, applicants should clearly describe a plan for handling assays that need some modification for HTS (e.g., assay miniaturization and automated processing) and discuss criteria for determining when an assay is sufficiently optimized to allow HTS or when an assay cannot be implemented in HTS. Applicants should describe the assay development and implementation capabilities that they currently have or plan to have by the start of the award to accept a variety of assays from the scientific community and adapt them to a high throughput format. Issues such as experience with assay optimization, throughput, reproducibility, validation, cell culture, protein or vector production, and other relevant capabilities should be discussed. Prior experience of the center PD/PI with performing successful HTS on assays generated outside the center PD/PI’s laboratory should also be described. Screening centers should have the capability to provide scale up of reagents for HTS as this requirement is often beyond the means of assay providers. This would include methods to purify protein and the necessary equipment to grow large numbers of cells in culture.

F1b. HTS Implementation (applicable to Comprehensive and Specialized Screening Centers). A production center will need to be able to successfully carry out HTS using robotic technologies and high throughput detection systems capable of measuring a variety of readouts (e.g., absorbance, fluorescence, luminescence, FRET, BRET, SPA, etc.). Given the number of compounds to be screened, 96-, 384- and/or 1536-well plate reader capabilities will be required. Centers will need to be able to validate HTS-based assay results using appropriate statistical controls, positive and negative controls, and ways to limit and identify false positives and false negatives. In most cases, hit-confirmatory assays and at least one secondary screen (submitted by the referring investigator) will need to be run to identify true positives that would be candidates for further development as probes. Applicants should justify each of the HTS component technologies proposed for inclusion in the screening center in terms of how each one will be utilized as an integral component of the center’s HTS capabilities. Applicants should also present a coordinated, viable plan for monitoring costs accurately, reducing the use of reagents and MLSMR compounds and, when appropriate, for implementing advances in detection, miniaturization, and robotics required to maintain the center at state of the art and to meet the growing increase in screening demand as the MLSMR continues to expand the screening library.

F1c. SAR Analysis and Medicinal Chemistry (applicable to Comprehensive and Specialized Chemistry Centers). It is essential that compounds identified as research tools for the investigation of particular targets and biological processes by the MLPCN are reliable and capable of providing reproducible and accurate information on the activity of their intended targets. The probe compounds produced by the centers will need to be usable by the research community for in vitro studies. In most cases, compounds identified by initial screening (“hits”) will not be ideal as research tools. It is likely that properties such as affinity, specificity, and solubility will need to be improved before a useful compound is obtained. Therefore, applications for the Comprehensive and Specialized Chemistry Centers should describe a plan for the development or acquisition of sufficient computational and synthetic chemistry capability to generate a library of structurally related compounds around a confirmed hit and how to test those compounds in the appropriate assays to identify derivatives with improved affinity, specificity, solubility, and bioavailability. It is also likely that hits would need to be re-synthesized at the center before structure-activity work is undertaken. Chemistry efforts could include optimization of SAR via directed library synthesis and structure-guided design or other appropriate methods. The minimum characteristics for a probe compound to be a useful research tool will be determined by the MLPCN Steering Committee and the MLP Project Team; it is anticipated that such characteristics will include <100 nM affinity, >100-fold selectivity against related targets, and solubility in aqueous solutions or in a low concentration of DMSO. NIH recognizes that whatever the characteristics of the probes, further modification may be necessary to produce compounds that are useful for in vivo studies (although such further modification is outside the scope of this FOA). For this reason, it is the desire of NIH that during the production phase, all probes and all related biological and chemical data will be made available to all researchers. The centers will be expected to provide 10-15mg quantities of probes and the analogs developed in the hit to probe optimization phase to the MLSMR. NIH is working to develop a process outside the MLPCN intended to facilitate general access to probes by the biomedical community.

F1d. Screening Informatics (applicable to Comprehensive and Specialized Screening Centers) and Cheminformatics (applicable to Comprehensive and Specialized Chemistry Centers). Adequate informatics capabilities will be critical to multiple components of the center. Depending on the type of center, automation, sample tracking, laboratory procedures, quality control, data management, deposition of screening data, assay protocols, and other relevant information to PubChem, and data analysis all depend on sufficient informatics capabilities and resources. Applicants should present a clear set of operational plans for ensuring that, as appropriate, the screening and cheminformatics needs of the center are addressed, and demonstrably contribute to the efficiency of the center’s operation. Issues that should be addressed include plans for acquisition and analysis of primary screening data, and data generated from screening of a second-generation library of structurally related compounds generated around a confirmed hit. Comprehensive Center and Specialized Chemistry Center applicants should additionally describe their capabilities for computational chemistry, and cheminformatics to fully support the hit-to-probe work. In preparing the screening and/or cheminformatics plan, the applicant should take into account that once the MLPCN is established, the MLPCN Steering Committee will address issues of possible standardization of operating procedures across centers such as quality control and quality assessment for assay and screening procedures, and data deposition practices for submission of screening data, assay protocols, and standards of information transfer to PubChem. Applicants will be expected to demonstrate a high degree of flexibility and willingness to adopt uniform policies and procedures recommended by the MLPCN Steering Committee.

All screening data and descriptions/protocols for assays optimized for HTS by the MLPCN are required to be deposited immediately in the public domain (via PubChem) after they have been confirmed for accuracy. The procedures for the deposition of screening data and assay protocols to PubChem will be jointly managed by the MLPCN network, PubChem and NIH program staff. For chemical structure data, PubChem currently supports multiple formats such as SDF or MOL files. For chemical synthesis descriptions of small molecules in the Repository, PubChem supports deposition of text descriptions and citations. Centers performing chemical synthesis are welcome to propose solutions for establishing an online database of reaction protocols.

F1e. Administration and Management. Each MLPCN center must have a well-conceived and implemented management plan and a significant commitment of effort by the PI of the project. The PI of an MLPCN center is expected to devote at least 25% effort to the project. The application should describe the management plan for the proposed center, and how the plan will support its proposed goals. It should describe the organization of the proposed center and its management structure, and should address the integration of the functional components to form an efficient assay optimization, screening, and/or hit optimization chemistry pipeline for generating small molecule research tools. The plan should specifically address interactions between key personnel and reporting relationships. Applicants must discuss the ways in which close working interactions will be promoted and maintained in cases where the key personnel on a given project will be at geographically distinct performance sites (as will always be the case for Specialized Screening or Chemistry Centers). Recruitment and training of personnel should be discussed. The plan should specifically address how any collaborations or subcontracts will be managed. The PI is strongly encouraged to propose a project manager for the center to manage the day-to-day operations. All center applicants are expected to apply process management methods for planning, monitoring and managing the portfolio of assays and probe development projects (as appropriate) over the lifetime of the grant period and are expected to communicate this to NIH program staff upon request.

The management plan should also address the interactions of the proposed center with the other components of the MLPCN (e.g., MLSMR, the MLPCN Steering Committee, the NIH program staff; these components are described in more detail below) and how the center would structure collaboration with the assay providers and in certain circumstances, compound contributors.

NIH does not specify how core functions are to be organized within the center. The applicant may choose to organize the proposed center in terms of separate functional cores or in any other manner deemed appropriate for the implementation of an effective pipeline. However, the application must clearly address how the proposed organization of the center will ensure that each of the core functions is effectively accommodated. Each of the functions is described in more detail below.

F2. Requirements for Center-driven Research Project. Each type of center is invited to propose a creative, highly innovative research program of up to 6 years with a well articulated vision for advancing the ability of the academic biomedical community to create and use small molecules for the investigation of important and unmet challenges in biomedical research. The proposed projects must be distinct from investigator-provided assays and must not be merely an extension of on-going research work in the applicant’s laboratory. Both the vision and the proposed high impact/high payoff projects should leverage the unique strength(s) of the particular center.

Proposals for the center-driven projects must provide the following information: a) a clearly stated vision of what will be achieved at the end of the funding period; b) a clear articulation of how the success of the vision will have a broad impact on molecular and cellular biology and on the increased use of small molecules as probes of biomolecular systems; c) a description of how the proposed project(s) and their specific aims address the vision; d) a defined plan for the proposed project(s) and sub-projects with timelines that have milestones with sufficient detail for evaluation and monitoring purposes; e) one or more alternative approaches as a back-up if the initial plan were to fail; and f) a description of a method to measure progress and milestone achievements quantitatively and qualitatively over the course of the research project(s). Applicants may request up to 30% of the maximal allowed budget per year be dedicated to this center-defined research project over the grant period of 6 years.

In addition to the customary NIH annual progress reports, the center-driven programs will be evaluated at two-year increments. Evaluation of both project progress and continuing importance of the original program goals will be carried out by the ESP and NIH program staff, with input from outside experts as appropriate, at the end of the second year and the fourth year into the grant period. Funding for the center-driven components of the U54 cooperative agreement may be adjusted annually and on the basis of the outcome of that review.

In addition, the center-driven and user-driven components of each center will be evaluated as part of the overall MLP Mid-course Review that will occur near the end of the third year of the grant period. These evaluations and outcome of the mid-course review will be crucial in establishing a specific, concrete and successful set of outcomes for the MLPCN over the 6 year project period.

G. Other Considerations.

In addition to the functions described above, there are a number of other issues important to the successful operation of the MLPCN that should be addressed separately in the application:

G1. Acquisition of Assays and Outreach. The function of the MLPCN centers will be to receive assays that have been developed by members of the scientific community, adapt them for high-throughput implementation, and use them to screen the compound collection provided by the MLSMR to identify and confirm compounds that have the desired effect in the assay. Proposals for innovative assays for screening center implementation will be solicited from the scientific community through FOAs in the NIH Guide. Applications will be peer reviewed for scientific merit, including suitability for high-throughput implementation, by a Committee convened by the CSR.

The MLPCN screening centers have a key role to play in the acquisition of high quality assays by the Probe Production Center Network by mounting an active outreach effort about the opportunities provided by the Network to the larger scientific community. Applicants for Comprehensive or Specialized Screening Centers should address the issue of evaluating and adapting assays for high-throughput implementation and should present a clear plan for doing so. All center applicants should also provide an aggressive plan to reach out to the scientific community to encourage investigators to access the resources of the MLPCN. Success of this Roadmap initiative is dependent on the awareness and participation of the scientific community. The screening centers should describe plans to increase awareness of the MLP through meetings, presentations, networking and other means. Assays that are brought into the network through assay development collaborations (Assay Development for HTS, R21 program) with a center improve the chances for a successful X01 or R03 peer review and insure that the highest quality assays are screened in the MLPCN. Chemistry centers should provide an outreach plan to increase awareness in the chemistry community of the chemistry opportunities of the MLPCN and NIH’s interest in obtaining novel and unique compounds for its screening collection.

The results of the X01 and R03 reviews and information about available capacity and expertise at each center should form the basis for assay prioritization and assignment decisions. The information will be provided on a regular basis to the MLPCN Steering Committee, which will make recommendations about assay assignments. The MLP Project Team will provide a second level of review of the decisions of the Steering Committee and give final approval for assay assignments on a time frame suitable to the screening schedules of the centers. The previous interaction of a center, through its outreach component, with an assay provider will be taken into account in assigning the assay of interest.

The MLPCN centers will not have a privileged position relative to the rest of the scientific community with respect to access to HTS services. Should the PI or any outreach participant in an MLPCN center wish to implement his/her own assays, s/he will have to submit that assay for review and prioritization according to the process described previously for the scientific community. Should such an assay be placed on the priority list, the MLP Project Team will take the PI’s interest into account in assigning that assay to the requested center.

G2. Data Release. A major benefit provided by the MLPCN to the scientific community is the rapid dissemination of screening data. It is expected that MLPCN centers will quickly release data (i.e., screening data and assay descriptions) to PubChem as soon as the data have been determined to be reliable. It is anticipated that the MLPCN Steering Committee will develop guidelines for standardizing the reliability/validation of screening data for different types of assays across centers. Responses to this RFA should include a statement of willingness to abide by the immediate data release policy for submission of screening data to PubChem. MLPCN members will submit data to PubChem in the formats adopted by the MLPCN Steering Committee working with NIH program staff and PubChem staff at NCBI. These formats will leverage current practices and standards developed and/or adopted during the pilot phase of this Roadmap initiative (http://www.nimh.nih.gov/about/organization/dnbbs/the-mlscn-project-team-policy-on-data-sharing-and-ip-in-the-mlscn-program.pdf). For chemical structure data, it is anticipated that PubChem will support, among others, existing formats such as SDF or MOL files. For screening assay descriptions and results, it is anticipated that PubChem will support depositions based on best current technologies including XML exchange specifications. Upon submission to PubChem, all data will be made freely available to the entire research community in a form that would allow for redisplay and reanalysis, so that maximal utility of this research resource will be realized.

The NIH has identified the MLPCN as a community resource project as defined by the Fort Lauderdale meeting (http://www.genome.gov/Pages/Research/WellcomeReport0303.pdf), and accordingly expects that users of the data will respect the legitimate interests of the producers to analyze and publish their results by treating the data as unpublished information, until otherwise indicated. As with any unpublished data, it is expected that users will provide proper citation of the source of the data. It is our further expectation that publications that result from this unpublished data be approved by the contributors of the assay and non-commercial compound providers of active compounds who may elect to be part of the team of collaborators This includes the crafting/approving of the manuscript and co-authorship. The individual investigators within the MLPCN may publish the results of their own screening efforts. Neither these individual publications nor any MLPCN network publications should delay the other’s publications. The MLPCN network may publish global analyses of the results of the screening effort. MLPCN members will fully disclose algorithms, software source code, and experimental methods to the other members of the network for purposes of scientific evaluation and will be strongly encouraged to make them available to the broad research community.

G3. Cost Sharing This program encourages, but does not require cost-sharing with the applicant institution, biotechnology, pharmaceutical, or disease foundations to support infrastructure and reagent costs, especially in the transition phase of the program, as defined in the current NIH Grants Policy Statement. NIH is aware that a number of institutions have already established such activities and have already committed institutional funds to them. Cost sharing will not be a review criterion; any comments that reviewers might make will be reported in an administrative note for consideration by program staff.

G4. Transition Plan A fundamental objective of the NIH Roadmap for Biomedical Research is to transform the way in which biomedical research is done in the future because while “the opportunities for discoveries have never been greater, the complexity of biology remains a daunting challenge.” The Molecular Libraries Initiative, now Program, was implemented to effect a major change in academic and public-sector biomedical research by making the power of chemical genomics broadly available outside of the pharmaceutical sector. The role of the NIH Roadmap in this effort has been to provide the “incubator space” for this major initiative to develop and mature, and it has been appropriate, therefore, to provide the initial funding for the growth of chemical genomics capability through the Common Fund from which Roadmap projects are supported.

However, the planning of Roadmap projects includes the eventual transition of support from the Common Fund to individual NIH institutes and more traditional sources of funding as the transformative effects of the Roadmap project are realized. For the MLP, this transition will begin in the fifth year of the Program. The first four years of the Production Phase will be fully supported by the Common Fund; there will then be a two-year transition period in which the Common Fund contribution will decrease.

Therefore for purposes of the present FOA, applicants should provide a budget request for years -05 and -06 sufficient to support probe production at the same levels as in years -01 to -04. However, applicants should realize that the award of the two-year transition phase will be based on program priorities, on the availability of funds, and on successful completion of negotiated scientific milestones as determined by NIH staff in the context of the NIH Midcourse review.NIH staff will work with MLP awardees to identify additional funding sources that will allow continued support for the MLP. At the same time, applicants are well-advised to begin planning during the first few years of the award for other mechanisms of support, such as fee for service and/or private funding.

Notes: Other considerations including data sharing, cost sharing and transition plan will not be review criteria; any comments that reviewers might make will be reported in an administrative note for consideration by program staff and by the applicant.

Because of the complexity of the MLPCN, it is anticipated that program staff from NIH may visit each MLPCN center periodically to conduct an administrative site visit. Each center should also plan for hosting at least one meeting of the MLPCN Steering Committee and should budget appropriately.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This FOA will use the NIH U54 Specialized Center Cooperative Agreement award mechanism. In the cooperative agreement mechanism, the PI retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the PI, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".

2. Funds Available

The NIH Roadmap intends to commit approximately $70 million per year from the Common Fund for the first four years of the six year funding period (2008-2013) to support 6-10 centers. The earliest anticipated start date for awards under this funding opportunity is July 1, 2008.

The MLP anticipates awarding up to 2-4 Comprehensive Centers, 2-3 Specialized Screening Centers, and 2-3 Specialized Chemistry Centers. Comprehensive Center applicants may request up to $10 million direct costs annually; Specialized Screening Center applicants may request up to $2.1 million direct costs annually; Specialized Chemistry Center applicants may request up to $2.85M direct costs annually. The total project period for an application submitted in response to this FOA may not exceed six years. Funding of the MLP program beyond the initial 4-year production phase will be determined by successful completion of negotiated scientific milestones as determined by NIH, by the outcome of the NIH Midcourse review of the overall MLP program, and on the availability of funds.

Costs for equipment may be included in year one, up to $500,000. There will be no limit on equipment costs in the following years but should be well justified to meet the goals of the network.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size of each award will also vary. Although the financial plans of the NIH provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Section III. Eligibility Information

1. Eligible Applicants

This NIH Roadmap RFA is a limited competition for those who on the basis of peer review of PAR-07-368 (X02) applications have been invited to submit full U54 applications.

1.A. Eligible Institutions

For PAR-07-368 (X02) an organization with any of the following characteristics were eligible:

Public/State Controlled Institution of Higher Education
Private Institution of Higher Education
Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education)
Nonprofit without 501(c)(3) IRS Status (Other than Institution of Higher Education)
For-Profit Organization (Other than Small Business)
State Government; U.S. Territory or Possession
Domestic Institutions
Eligible agencies of the U.S. Government

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI was eligible to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities were, as always encouraged to apply for NIH support. Foreign investigators can serve as a PD/PI on a core, a member, or consultant for a center.

The timeline for the program is given below.

October 2007 Invitations are made for the U54 applications

January 10, 2008 Submission date for U54 full application

March, 2008 Scientific merit review for full application

May 2008 National Advisory Council review of application

June 2008 Awards announcement

July 1, 2008 Starting date for the Production Phase of the MLPCN

2. Cost Sharing or Matching

This program does not require cost-sharing as defined in the current NIH Grants Policy Statement

3. Other-Special Eligibility Criteria

Limited eligibility for the U54 applications in response to this FOA: Investigators interested in participating in the MLPCN must have submitted a pre-application (X02), as described in PAR-07-368 “Preapplication for the Molecular Libraries Probe Production Centers Network (MLPCN) [X02]”. Successful applicants have been invited to submit a U54 cooperative agreement application in response to this FOA. It is expected that the PD/PI for the X02 pre-application also will be the PD/PI of the U54 application. The U54 application can be submitted by a single institution or by a consortium of institutions. Only applicants who successfully competed in the pre-application process are eligible to compete for the MLPCN.

An individual can participate as the PD/PI of the center in only one application. There are no limits on the number of applications that can be submitted by one organization.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact Grants Info, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-0088.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Applications From federal Agencies

“The requests from federal agencies, including the NIH intramural program, will not include any salary and related fringe benefits for career, career conditional or other federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative costs).

In general, the budget requests will be limited to the incremental costs required for carrying out the proposed work. These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. While support for extramural collaborators may be requested in a separate grant application, funds can be requested for services by an external investigator or contractor as a subcontract/consortium including the applicable indirect (F&A costs) of the contractor/collaborating institution.

Justification must be provided for all requested support and for the Federal employees who will be committed to the project although no funds are requested in the application.

Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.”

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date: December 13, 2007
Application Receipt Date: January 10, 2008
Peer Review Date: March 2008
Council Review Date: May 2008
Earliest Anticipated Start Date: July 1, 2008

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

Descriptive title and abstract of proposed research.
Name, address, and telephone number of the PD/PI.
Names of other key personnel.
Participating institutions.
Number and title of this funding opportunity.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Ingrid Y. Li, Ph.D.
NIH Molecular Libraries & Imaging Roadmap
National Institute of Mental Health, NIH
6001 Executive Boulevard, Room 7192, MSC 9641
Bethesda, MD 20892-9641
Telephone: (301) 443-7099
FAX: (301) 402-4740
Email: ili1@mail.nih.gov

Applicants are strongly encouraged to send the letter of intent by Email. Please do not submit the same letter by multiple routes (e-mail, FAX, or hard copy)

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and five signed copies, as well as all of the appendix material are to be sent to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by NIH Roadmap staff. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the PI in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

Applications are to be submitted on Form PHS 398 (http://grants.nih.gov/grants/funding/phs398/phs398.html). All instructions and guidelines accompanying the PHS 398 are to be followed, with the exception of the sections modified by the specific instructions described below.

Research Plan Component for the U54 application:

It is recognized that the applications in response to this FOA will be longer and more complex than many other NIH applications. In order to ensure an effective review, the application should be clearly laid out and well organized into sections, the main function/center cores (See Section II.I.1.F1a-e) and the Center-driven research Project (see Section II.I.1.D and F2). The number of functional cores is determined by the type of center (see MLPCN Centers, Section II.I.1.C); http://mli.nih.gov/resources/MLPCN_X02_FAQ.htm).

a) Comprehensive Centers should describe five functional cores (1. Assay Development, Adaptation and Implementation, 2. HTS, 3. Chemistry, 4. Informatics, 5. Administration and Management, see Section II.I.1.C1) and the optional Center-driven Research component (Section II.I.1.D and F2).

b) Specialized Screening Centers should describe four functional cores (1. Assay Development, Adaptation and Implementation, 2. HTS, 3. Informatics, 4. Administration and Management, see Section II.I.1.C2) and the optional Center-driven Research component (Section II.I.1.D and F2)

c) Specialized Chemistry Centers will need three functional cores (1. Informatics, 2. Chemistry, 3. Administration and Management, see Section II.I.1.C3) and the optional Center-driven Research Project (Section II.I.1.D and F2). The informatics core must be able to interpret the data coming from the screening centers and use computational chemistry resources to provide a full SAR to support the medicinal chemistry development of probe leads.

Organization of the Application:

Applicants must construct the Research Plan component as a single document. The total page number for a Specialized Center application is 35 pages and the total for a Comprehensive Center application is 50 pages (in both cases, including the introductory overview). It is recommended that the Research Plan be divided into separate sections for the user-driven and center-driven components and the user-driven component be further subdivided into sections corresponding to the center cores with an average of 4-5 pages for each core. It is also recommended that the center-driven section not exceed 15 pages for a Comprehensive Center or 7-8 pages for a Specialized Center. Additional sections should address how the center will collaborate with members of the network, the plan for outreach to the research community, data sharing, cost sharing and the transition plan for additional mechanisms of funding for the center beginning in year 5.

The application should be organized as follows:

1. Form Page 1: Face Page

2. Form Page 1 – continued: N/A

3. Form Page 2: Description, Performance Sites, and Key Personnel.

4. Form Page 3: Table of contents

5. Form Page 4: Detailed budget for initial budget period.

Form page 4 should be provided for each of the functional cores, and for any subcontractual or consortium agreements. A separate overall budget for the whole center should also be prepared using form page 4.

6. Form Page 5: Budget for entire proposed project period.

Form page 5 should be provided for each of the functional cores. A separate overall budget for the whole center should also be prepared using form page 5. Since form Page 5 only provides a 5-year budget period, a continuation form Page 5 should be used for the 6^th year budget request.
The budget justification beginning on form Page 5 should include a detailed justification for key personnel. As part of the justification, the person months that all staff are spending on each functional unit should be specified. A detailed budget justification should also be provided for any sub-contractual or consortium agreements.
A detailed justification should also be supplied for each piece of capital equipment over $25,000 requested for the center. Equipment costs are allowable up to $500,000 in year one. No limit is placed on the allowable costs for equipment in the second and third years, but equipment costs should be well justified.

7. Biographical Sketch Format Page: Should be provided for each of the key personnel.

8. Resources Format Page:

Complete the resources section for each of the functional cores. Describe the features of the institutional environment that are or would be relevant to the effective implementation of the proposed MLPCN program. As appropriate, describe available resources, such as equipment, cell culture facilities, laboratory facilities, participating and affiliated units, geographical distribution of space and personnel, and consultative resources. Include a letter documenting institutional commitment to the MLPCN program, including provision of funding, space, faculty positions, and/or commitments for construction or renovation. Use continuation pages as needed.

9. Continuation Form: Use this form for the Research Plan pages, including introductory overview, background and significance specific aims, preliminary studies/progress report, research designs and methods for each of the proposed functional cores.

In the Research Plan-- user-driven section of the application, the applicant should clearly describe existing capabilities, plans for acquiring additional needed capabilities, and a clear plan for any necessary scaling up of those capabilities in the first year of the production phase. The center must have the capacity to screen, at minimum, 300,000 compounds in the MLSMR in 25 assays for Comprehensive Centers or in 5 assays for Specialized Screening Centers per year by no later than the end of the first year. Specialized Chemistry Centers will need to have the capacity to handle minimally 10-15 probe projects per year.
In the Research Plan- center-driven section of the application, the applicant should clearly state: a) a clear vision of what will be achieved at the end of the funding period; b) articulate clearly why success of the vision will have a broad impact on molecular and cellular biology and the use of small molecules as probes of biomolecular systems; c) describe how the proposed project(s) and their specific aims are integrated together into the vision; d) define a plan for the proposed project(s) and sub-projects with timelines and place milestones along the timeline in sufficient detail for evaluation and monitoring purposes; e) describe an alternative approach if the initial plan were to fail; and f) describe clearly a method to quantitatively measure progress and milestone achievements over the course of the research project.

Introductory Overview/Specific Aims/Background and Significance (2-5 pages):

Clearly identify the type of center for which the applicant requests funding (Comprehensive Center, Specialized Screening Center, or Specialized Chemistry Center). Provide an overview of the proposed center and describe how it can contribute to the MLPCN to achieve the overall goals of the MLP. List specific aims and milestones for the first year and projected milestones for subsequent years of the program. In subsequent years, milestones will be reconsidered each year in negotiation with NIH program staff. Specific Aims of Overall Center: Describe the center goals. Explain the proposed contribution of each of the functional cores in achieving the objectives of the center. The Overview must contain a Summary Table with all of the functional cores in the Center. This section should also address the data sharing and willingness to collaborate with the MLSMR, assay provider, compound provider, other centers, etc.

For each Center Core include the following:

Provide a brief overview of each functional unit, its activities, and how the key personnel will interact and coordinate with the other functional cores.

Preliminary Studies/Progress Report.

For screening centers, the Preliminary Studies/Progress Report section of the Research Plan should provide a summary data table providing information on the center’s progress in the last two years. Provide information in two columns for the period September 2005 to August 2006 and September 2006 to August 2007. This information should include the number of assays implemented, number of compounds screened in each assay, the number of probe projects undertaken and number of analogs generated for each project, the chemical probes generated, deposition of data to PubChem or similar public database, and any resulting publications. Provide additional detail on one or more assay(s)/probe project(s) to illustrate the current capability and capacity of the center. Screening Center applicants should describe the capabilities that they currently have to import a variety of assays and adapt them to run on the center’s high throughput screening platform and the ability of the informatics core to accept, analyze and store large amounts of screening data. For Specialized Screening Centers, in addition to the above information, define areas of expertise and describe advantages of the center’s screening program to handle unique and/or difficult assays.

For Specialized Chemistry Centers, describe expertise with different types of chemistry, provide examples of hit optimization campaigns, describe plans for accepting and processing hits and plan for the communication and transfer of material and information with the screening centers. Describe experience in meeting milestones. For centers that were funded as part of the MLSCN, describe milestones met and compliance with the MLP data sharing and IP policy.

Research Designs and Methods.

Identify each proposed functional core by title and provide detailed information on each core, including those that are found to be underdeveloped for HTS. Provide current production rates and established QC, QA standards. Describe each core’s activities, and how the key personnel from that core will interact and coordinate with the other functional cores. What criteria will be used to determine if an assay should undergo further development at the center or be rejected and what steps will be required to determine rejection of the assay or modification to enable HTS? Explain the proposed contribution of each of the functional cores in achieving the objectives of the center.

When describing the Assay Development core, provide a plan for processing assigned assays that are found to be underdeveloped for HTS. What criteria will be used to determine if an assay should undergo further development at the center or be rejected and what steps will be required to determine rejection of the assay or modification to enable HTS?
When describing the Assay Adaptation/Implementation core provide a plan to implement a diverse array of both target-based, reporter and phenotypic assays to HTS format in the case of a Comprehensive Center, or a plan to implement a specific type of assay in the case of a Specialized Screening Center.
When describing the Screening Core, describe the core capabilities and provide a plan to screen the 300,000 or more compounds that will be in the MLSMR.
When describing the Informatics Core, provide a plan for informatics support to track compounds, assays, and screening data. Describe methods for data storage, retrieval, backup and recovery of data.
When describing the Chemistry Core, provide a plan for cheminformatics, SAR analysis and synthetic medicinal chemistry to optimize screening hits into useful in vitro and/or in vivo biological probes. Cheminformatics should include the ability to do similarity structure searches and SAR analysis.
When describing the Administrative Core, provide an operational plan for managing the center and organizing incoming projects; including a plan to collaborate with other MLPCN centers, the MLSMR, assay providers, non-commercial compound providers and the MLP Project Team.

Identify the center-driven component by title and provide detailed information on each proposed project. Clearly state the following points.

a clear vision of what will be achieved at the end of the funding period;
articulate clearly why success of the vision will have a broad impact on molecular and cellular biology and the use of small molecules as probes of biomolecular systems;
describe how the proposed project(s) and their specific aims are integrated together into the vision;
define a plan for the proposed project(s) and sub-projects with timelines and place milestones along the timeline in sufficient detail for evaluation and monitoring purposes;
sub-projects with timelines and place milestones along the timeline in sufficient detail for evaluation and monitoring purposes;
describe how key personnel will interact with the over all center.

Letters of Support.

Include a letter documenting institutional commitment to the MLPCN program, including provision of funding, space, faculty positions, and/or commitments for construction or renovation. A letter from an appropriate institutional official, generally a dean or provost, should follow the Research Plan. If multiple institutions are involved in the center application, a letter should come from each institution.

Appendix:

NIH has published new limitations on grant application appendix materials to encourage applications to be as concise as possible while containing the information needed for expert scientific review. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html

The following materials may be included in the Appendix

Up to five publications, manuscripts (accepted for publication), abstracts, patents, or other printed materials directly relevant to the proposed program. Do not include manuscripts submitted for publication. See NOT-OD-06-053.
- Publications in press: Include only a publication list with a link to the publicly available on-line journal article or the NIH PubMed Central (PMC) submission identification number. Do not include the entire article.
- Manuscripts accepted for publication but not yet published: The entire article may be submitted electronically as a PDF attachment.
- Manuscripts published but for which a publicly available online journal link is not available: The entire article may be submitted electronically as a PDF attachment.
- Probe reports that provide justification for the probe designation and description of how the compound was identified, supporting screening data on the compound demonstrating potency and specificity for the target, and if applicable, synthetic protocols.
Graphic images provided that the image (which may be reduced in size) is also included within the (stated) page limit of Items 2-5 of the Research Plan component. No images may be included in the Appendix that are not also represented within the Research Plan.

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the relevant policies and procedures may be delayed in the review process.

7. Plan for Sharing Research Data

During the pilot phase, the MLSCN/MLPCN developed a policy in consultation with the research community on data sharing and IP applicable to achieving the goals of the MLI (i.e., the NIH Policy on Data Sharing and IP in the MLP, http://www.nimh.nih.gov/dnbbs/datasharing-ip.pdf). During the production phase, the MLP Project Team expects that the existing policies will be followed. Consistent with such policy, all data generated by the MLPCN will be deposited into PubChem upon data verification. For this, the term “data” will include, but will not be limited to, assay descriptions, protocols and/or links to published assays implemented in the MLPCN; performance data for assays and compounds; primary data from HTS and data generated in the secondary screen (e.g., EC50s, IC50s, AC50s, counter screens); chemical structures, links to published or unpublished synthesis protocols for chemical analogs of non-commercial hits, or probes, and the biological activities of analogs and chemical probes.

All applicants are expected to include a statement of willingness to abide by the NIH Data Sharing and IP policy in the MLP and include a plan for sharing any other types of research data in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

8. Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources other than those addressed in the NIH Policy on Data Sharing and IP in the MLP (http://www.nimh.nih.gov/about/organization/dnbbs/the-mlscn-project-team-policy-on-data-sharing-and-ip-in-the-mlscn-program.pdf) will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans in meeting the programmatic goals will be considered by the MLP Project Team and MLIIG when making funding decisions (see Part I, Section IV, 2.A.2).

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.