Notice Number: NOT-RM-11-001
Release Date: October 8, 2010
National Human Genome Research Institute (NHGRI) and National Institute of Mental Health (NIMH) on behalf of the NIH Common Fund (Roadmap) Molecular Libraries Program
The purpose of this notice is to announce a Fast Track Program by which applicants with hit-to-probe optimization projects can submit a request for access to the probe development chemistry resources of the NIH Common Fund (Roadmap) Molecular Libraries Probe Production Centers Network (MLPCN).
The Molecular Libraries Probe Production Centers Network (MLPCN), a component of the NIH Common Fund (Roadmap) Molecular Libraries and Imaging Initiative, is a nationwide consortium of small molecule centers that produces innovative chemical tools for use in biological research. The MLPCN solicits novel assays from the research community for high throughput screening (HTS) against a library of 350,000 chemically diverse small molecules maintained in a central molecule repository (the Molecular Libraries Small Molecule Repository; MLSMR). Validated screening hits are optimized by medicinal chemistry to produce useful in vitro chemical probes. All of the results from the MLPCN’s activities are deposited into an open access database, PubChem, for use in studying biology and disease.
The MLPCN brings together over 100 medicinal chemists from five academic institutions and the NIH intramural research program at NHGRI to focus on the development of high quality probes from screening hits. The lead medicinal chemists have extensive industrial experience from both biotech and large pharmaceutical companies. These individuals have a strong record of delivering high impact probes, with more than 170 probes identified since the network was formed. MLPCN probes cover highly diverse targets, biology and disease areas with many probes moving on as potential leads in drug discovery efforts after exiting the MLPCN. The MLPCN has over 50 active medicinal chemistry projects in hit-to-probe optimization, with the capacity to undertake many more projects. Details on specific medicinal chemistry capabilities can be found at http://mli.nih.gov/mli/mlpcn/mlpcn-probe-production-centers/.
The scientific community obtains access to the national MLPCN resource through multiple peer-reviewed mechanisms applicable to: HTS-ready projects (Solicitation of Assays for High Throughput Screening (HTS) in the Molecular Libraries Probe Production Centers Network (MLPCN) (R03)); HTS assay development (Assay Development for High Throughput Molecular Screening (R21) , Development of Assays for High-Throughput screening for use in Probe and Pre-therapeutic Discovery (R01)); or via the Fast-Track mechanism (Notice of Opportunity for Fast Track Entry of Assay Projects for High Throughput Screening into the NIH Roadmap Molecular Libraries Probe Production Centers Network).
With this notice, NIH is soliciting projects to directly access medicinal chemistry resources provided by the MLPCN via the Fast-Track mechanism. NIH investigator-initiated and institute-sponsored projects and activities that are currently active but lack sufficient medicinal chemistry support for the development of small molecule probes are eligible to apply for Fast-Track entry to access MLPCN resources (see Resources Provided by the MLPCN below).
Active compounds identified through HTS ( hits ) can provide the starting point in the design of powerful research tools (probes) that allow pharmacological probing of basic biological mechanisms. The probes can be used to establish the role of a molecular target in a disease process. Hits from the HTS are validated in a specialized set of low-throughput biological/functional assays to eliminate false positives and are called validated hits . Validated hits can be derived from biological assays against a target or phenotype of interest. Medicinal chemistry efforts start with validated hits and chemistry optimization begins with the generation of analogs in order to identify chemical features of these hits ( chemical scaffolds ) that contribute to the useful attributes needed in a small molecule probe, such as affinity and selectivity for a target. This constitutes the first steps towards establishing structure-activity-relationships (SAR). After the completion of this step, further rounds of chemical synthesis and biological testing eventually results in small molecule probe(s) that are useful biological tools and may constitute starting points for drug discovery. Criteria that define MLPCN probes can be found at http://mli.nih.gov/mli/mlpcn/documents-definitions/?dl_id=149. Probes identified by the MLP can be found at http://mli.nih.gov/mli/mlp-probes/.
To be eligible, currently funded grants or projects should have:
1. Scientifically reviewed and funded aims to support the development of assays (primary, secondary and counter-screening) for use in small molecule discovery, the discovery of small molecule probes, or preclinical drug discovery.
2. Well-characterized small molecule compounds (validated hits) that could be a starting point for medicinal chemistry optimization.
a. A validated hit must elicit a reproducible response in at least two assay types and also elicit a dose-response over a ten-fold concentration range; demonstrate a potency of < 1 micromolar (for example, IC50 or EC50); demonstrate biological activity across related chemical analogs; provide a tractable starting point for optimization with no obvious major chemical liabilities, and reasonable evidence of mechanism; and specificity, as demonstrated by secondary and counter-screen assays to rule out experimental artifacts.
b. In order to maximize the MLPCN medicinal chemistry resources, complete screening data must be provided upon acceptance of the project.
3. Chemically tractable validated hits
Applicants are strongly encouraged to contact Program staff (see below) to discuss the appropriate utilization of this Fast-Track mechanism with respect to eligibility and the details of the submission requirements.
Applications can be made anytime during the year. NIH intends to accept approximately ten new projects per year using this mechanism.
Proposals should be submitted to the staff listed below, using the standard format found at http://mli.nih.gov/mli/mlpcn/documents-definitions/?dl_id=1212 .
Project proposals should include:
Title:
PI(s) and Institution(s):
Grant Number:
Project end date of parent grant from eRA Commons:
Chemistry Fast Track Submission Date:
Parent Grant Aims and Goals:
Grant Progress Report:
Brief summary of the project or subproject that resulted in the validated hits proposed as starting points for optimization.
Desired Probe Characteristics:
a. Impact of Proposed Probe:
Briefly describe the potential impact of the proposed probe:
- What limitations in current state of the art will the proposed probe address?
- What will the proposed probe be used for?
- Who in the research community will use the proposed probe?
- What is the relevant biology to which the proposed probe can be applied?
b. Proposed Probe Attributes:
- Describe the required attributes of the proposed small molecule probe, including properties such as affinity, activity, specificity and selectivity. Describe how these attributes will be measured.
Prior Art:
A thorough prior art search, including compounds reported in the patent literature, is required. Structures of known compounds with the desired activities must be presented. References must be provided for all prior art compounds.
Assays
- Describe all assays to be used, including itemized protocols. Include references to publications describing the proposed assays. The proposed in vitro testing methodologies must already have been developed and validated. A small molecule probe confirmation assay should be proposed as a final validation step to demonstrate the probe’s utility in the system in which it will be used.
Chemical Structures and biological properties of validated hits and analogs:
Provide the chemical structure, proof of identity, and purity analysis for each validated hit and analog proposed as a starting point for the project. Include relevant preliminary data from primary, secondary, and selectivity assays for each validated hit and analog. Biological activity must have been demonstrated with more than one batch of the compound.
Critical Path Flow Chart:
- Construct a simple scheme of the proposed Critical Path (see http://mli.nih.gov/mli/mlpcn/documents-definitions/?dl_id=941 for examples. Include a panel of in vitro primary, secondary and selectivity assays, each capable of measuring the activity of a test compound leading to the desired probe attributes. The applicant should be capable of running these assays at a throughput that would support the proposed chemical analog testing program. It is expected that applicants will have the ability to rapidly test 20-40 compounds per month to enable iterative rounds of chemical optimization.
References
Applications should be submitted using the standard format found here. Applications not using the standard format and/or missing requested information may be returned without review.
The NIH Common Fund (Roadmap) Molecular Libraries Project Team will undertake a technical review of the application. This will include a review of the progress report for the funded grant as well as the detailed information provided by the applicant in response to this notice. Applicants can expect a final decision within 2 months of application. The NIH intends to accept approximately 10 new projects per year using this mechanism. Final decisions on acceptance will be made based on the following factors:
- Results of the technical review.
- MLPCN portfolio balance including novelty of the target and/or disease relevance.
- Willingness of the applicant to abide by the MLPCN data release policies.
- Availability of MLPCN medicinal chemistry resources.
- Congruence with the scope of the MLP Program.
MLPCN medicinal chemists will carry out hit-to-probe optimization, with the goal of developing one or more chemical series demonstrating a mature SAR; a selectivity profile in pharmacologically relevant in vitro models; and, if accepted for extended characterization (see below), additional/deeper biological testing. Accepted proposals will enter the MLPCN probe development pipeline and will be executed as collaborations between the MLPCN and the applicants. Each project begins with the creation of a Compound Probe Development Plan (CPDP) that contains rigorous "go/no-go" decision points developed in collaboration with the PI of the project, the scientists within the MLPCN center, and NIH Science Officer. Projects with validated, chemically tractable hits will receive one to two rounds of medicinal chemistry.
The MLPCN will:
- Provide cheminformatics and molecular modeling support.
- Develop the synthetic strategy for the preparation of analogs.
- Design and make specific analogs to optimize potency and/or selectivity.
- Provide chemical samples for testing in investigator's laboratory.
Successful projects can, at a future date, be considered by the MLPCN Project Team for generating "extended characterization probes". Such extended characterization can include additional/deeper biological testing, such as testing in multiple cellular systems; ex vivo (e.g., tissue preparations) and in vivo systems (existing, relevant animal models); and determination of the mechanism of action if unknown. Details of "extended characterization projects" can be found here.
It is important to note that Fast Track applications constitute a request for access to MLPCN medicinal chemistry resources and will not result in direct investigator funding. Investigators interested in accessing these resources will need to conduct biological screening of compounds produced by the MLPCN medicinal chemistry efforts. Data from those assays must be provided to the MLPCN chemists in order to optimize the proposed probes.
Please direct all inquiries to:
Enrique Michelotti, PhD
Chemistry Program Chief
NIH Molecular Libraries Program
National Human Genome Research Institute
Neuroscience Center/Room 7207
6001 Executive Blvd, Bethesda, MD 20852
Telephone: (301) 443-5415
FAX: 301-443-1731
Email: [email protected]
and Human Services (HHS)
