Advancing Treatment Options using Targeted Degrader Technologies

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Topic Description

Post Date: March 23, 2026

Expiration Date: March 10, 2027

This topic encourages studies that develop and apply degrader technologies to target disease-associated factors across a range of pathologies.

A major emphasis is the development of therapeutics that selectively eliminate toxic proteins. Traditional strategies for diseases such proteinopathies aim to restore proteostasis by modulating protein synthesis, folding, aggregation, and degradation; however, these approaches have had limited success, and many dysregulated proteins remain difficult to target due to structural complexity. Emerging targeted protein degradation (TPD) platforms expand therapeutic opportunities by enabling the selective removal of pathogenic proteins. These approaches include proteolysis-targeting chimeras (PROTACs), molecular glues, and hydrophobic tag tethering degraders (HyTTDs) that engage the ubiquitin–proteasome system (UPS). Other strategies, such as lysosome-targeting chimeras (LYTACs) and antibody-based PROTACs (AbTACs), leverage lysosomal pathways including endocytosis, phagocytosis, and autophagy, further broaden the types of proteins and pathogenic factors that can be targeted for degradation. 

Recognizing the versatility of nucleic acid–based approaches, RNA-targeted chimeras (RIBOTACs) and antisense-mediated degradation further expand the therapeutic toolkit for targeting diverse pathogenic processes.

This topic encourages studies that advance novel targeted degrader technologies, identify specific and druggable targets, and establish translatable preclinical biomarkers to monitor disease progression and predict therapeutic response. Complementary mechanistic studies investigating the cellular toxicity of factors amenable to degrader-based interventions are also within scope.

This topic is being issued as part of the Make America Healthy Again initiative, which is expanding NIH and agency research into specific areas.

Participating ICOs

National Eye Institute (NEI)

Several eye diseases are associated with misfolded protein aggregates, including various forms of retinitis pigmentosa, maculopathies, glaucoma, cataracts and corneal dystrophy. The NEI seeks research in scope including the use of organoids, computational models, microphysiological systems and other novel approach methodologies (NAMs) to advance our understanding of the mechanisms by which eye disease-associated proteins misfold and to develop treatments to improve vision. 

Areas of interest include, but are not limited, to:

  • Identifying key and intermediate species of toxic misfolded proteins and their aggregates
  • Identifying protein-chaperone interactions and therapeutics that can rebalance the proteostatic network.
  • Developing TPD-based therapeutics
  • Developing translatable preclinical biomarkers
ICO Scientific Contact:
Lisa Neuhold, Ph.D.
[email protected]

Tiffany Cook, Ph.D.
[email protected]

Neeraj Agarwal, Ph.D.
[email protected]

National Cancer Institute (NCI)

NCI supports projects on:

  • Novel therapeutic approaches to target overexpressed or hyperactivated oncoproteins
  • TPD approaches that include PROTACs, LYTACS, and molecular glues

NCI is interested in applications on:

  • Improving efficacy, absorption, distribution, metabolism, and toxicity profiles of PROTAC and related drugs using NAMs
  • PROTAC linker chemistry
  • Expanding these technologies to modulate targets that have not been amenable to traditional drug targeting approaches 

NCI also encourages studies elucidating TPD mechanisms associated with PROTAC uptake in cancer cells, proteasome overload, solid tumor penetration, tumor microenvironment effects, off-target activity, and resistance. 

Areas of interest include studies employing in vitro and in vivo models, computational/mathematical approaches, synthetic biology, physical sciences, and development of tissue-selective and reversible PROTACs.

ICO Scientific Contact:
Sundaresan Venkatachalam, Ph.D. (Preclinical Therapeutic Areas)
[email protected]

William Greenberg, Ph.D. (Preclinical Therapeutic Areas)
[email protected]

Ruibai Luo, Ph.D. (Cancer Cell Biology)
[email protected]

Cindy W. Kyi, Ph.D. (Technology Development)
[email protected]

National Institute of Allergy and Infectious Diseases (NIAID)

NIAID is very interested in developing targeted degradation strategies against viral, bacterial, fungal and parasitic pathogen components, including mechanisms essential for pathogen replication, survival, and virulence—such as toxins, their receptors, as well as prion proteins causing prion-associated diseases.

NIAID aims to support projects that:

  • Identify key pathogen and associated host targets suitable for degradation.
  • Integrate emerging technologies such as PROTACs, molecular glues, and LYTACs, to expand the range of druggable targets as well as treatment strategies.
  • Discover and evaluate highly selective ligands against pathogen and host targets, inducing proximity to degradative machinery.
  • Enhance the drug-like properties of degraders to maximize therapeutic benefit (e.g., improved pharmacokinetics, cell permeability, and oral bioavailability).
    • Develop degraders against non-protein targets, e.g., RNA, RiboTACs), and other novel approaches.
ICO Scientific Contact:
Raymond Slay, PhD
[email protected]

National Institute of Dental and Craniofacial Research (NIDCR)

Craniofacial development and morphogenesis relies on proper protein expression, processing, translocation, function, and degradation. Disruptions in these processes can lead to defects in the development of the craniofacial complex. For example, in dental diseases, the tooth formation process is disrupted as proteins accumulate intracellularly or are nonfunctional in carrying out their physiological role of ion translocation, resulting in poor enamel and dentin mineralization.  

NIDCR areas of interest include, but are not limited, to:

  • Identifying key and intermediate species of misfolded, mislocalized, or nonfunctional proteins or their aggregates that impact dental, oral, and craniofacial (DOC) development
  • Identifying dysfunctional protein-chaperone interactions and/or pathways that lead to protein disruption in the DOC complex
  • Developing targeted therapeutics correcting causative protein defects in affected DOC tissue
IC may give special consideration to support meritorious applications in this topic area.
ICO Scientific Contact:
Jason Wan, PhD
[email protected]

Zubaida Saifudeen, PhD
[email protected]

Alicia Chou, MS
[email protected]

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