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Development and Mechanist Validation of Next Generation Allosteric PRC2 Inhibitors for Cancer Epigenetics

Award Number: R16GM165744
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/17/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Development and Mechanist Validation of Next Generation Allosteric PRC2 Inhibitors for Cancer Epigenetics - Despite advances in oncology, there remains an urgent need for innovative anticancer strategies that can overcome resistance and improve patient outcomes. Epigenetic dysregulation is a key driver of tumorigenesis, with aberrant gene silencing and altered chromatin architecture contributing to cancer progression. Among epigenetic marks, trimethylation of lysine 27 on histone 3 (H3K27me3), installed by the polycomb repressive complex 2 (PRC2), is strongly linked to poor prognosis in diverse malignancies. Hyperactivation of PRC2, particularly through EZH2 overexpression, leads to widespread repression of tumor suppressor genes, driving cancer cell proliferation and therapeutic resistance. Although current PRC2 inhibitors mostly target the EZH2 catalytic domain, prolonged use frequently induces resistant mutations that limit clinical efficacy.To address this challenge, our laboratory has identified DAB003-8C, a potent and cell-permeable stapled peptide designed to target the SANT1L domain of EZH2, offering a first-in-class allosteric mechanism of PRC2 inhibition. This proposal aims to systematically optimize DAB003-8C and its derivatives through structure-activity studies, strategic chemical modifications, and computational design—yielding analogs with enhanced potency, stability, and permeability. Mechanistic investigations will clarify their allosteric inhibition and selectivity, employing biochemical and biophysical assays, protein-binding studies, cellular imaging, and stability assessments. Complementary cellular assays will probe the impact of these compounds on H3K27me3 levels, EZH2- mediated pathways, and gene expression profiles in a range of cancer cell models, integrating functional readouts such as proliferation, survival, and migration. Ultimately, this research will generate mechanistic insight into allosteric control of PRC2 and advance the development of next-generation inhibitors with broad translational relevance. The project will deepen our understanding of epigenetic regulation in cancer and facilitate the future discovery of targeted chemotherapeutics for overcoming resistance and improving patient care.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $154,500 )
2026	2026	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	2900 BEDFORD AVE	BROOKLYN	NY	11210	KINGS	USA	Biomedical Research and Research Training	000	1	7/17/2026	NEW	$154,500
														Subtotal = $154,500

Grand Total All Awards = $154,500

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Development and Mechanist Validation of Next Generation Allosteric PRC2 Inhibitors for Cancer Epigenetics

Award Number: R16GM165744

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/17/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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