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Chemical inducers of proximity to antagonize FOXA1

Award Number: R01CA303840
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/20/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Chemical inducers of proximity to antagonize FOXA1 - PROJECT SUMMARY/ABSTRACT FOXA1 is a prototypical “pioneer” transcription factor (TF) and essential lineage dependency for breast and prostate cancers. Its pioneer function is defined by the ability to bind cognate DNA motifs within closed regions of chromatin and then initiate local chromatin decompaction, resulting in de novo selection of cis-regulatory enhancer elements. In breast and prostate cancers, FOXA1 is also recurrently mutated, particularly within the Wing2 subdomain of its DNA-binding domain, which leads to altered DNA motif recognition and mis-localization of FOXA1 on the genome. Recently, we reported the chemoproteomic discovery of small-molecule covalent ligands that bind site-specifically and stereoselectively to cysteine-258 (C258) within the Wing2 subdomain of FOXA1. C258 is flanked by the most frequently observed cancer-associated alterations of FOXA1, demonstrating that this mutational hotspot also harbors a previously unrecognized ligand-binding site. Covalent ligands targeting C258 alter the motif preferences of FOXA1, causing it to gain and lose thousands of binding sites on the genome in prostate cancer cells. We found this neomorphic effect to resemble the mechanism of a proximally located recurrent prostate cancer mutation (R261G), suggesting that current FOXA1 ligands act in a neo-agonistic manner. We hypothesize that this newly discovered ligand-binding site can be repurposed to develop chemical inducers of proximity that antagonize FOXA1 function in prostate cancer cells. To address this hypothesis and more fully evaluate the potential for antagonizing FOXA1 with small molecules, we will: (i) synthesize heterobifunctional compounds that recruit transcriptional co-regulators to FOXA1 to corrupt its essential transcriptional regulatory functions in prostate cancer cells and (ii) develop molecular glues that can induce FOXA1 degradation. The development of molecular glue degraders will be accomplished using an innovative high-throughput chemistry (HTC)-based method for the prospective discovery of molecular glues, which we recently developed. Mouse xenograft models of prostate cancer are required for this project to evaluate the pharmacokinetic properties, in vivo pharmacodynamics, and anti-tumor efficacy of optimized FOXA1 chemical inducers of proximity within an intact tumor microenvironment, as these features are not yet recapitulated by available in vitro or computational new approach methodologies. Animal use is limited to the minimum cohorts needed to establish translational potential, consistent with 3Rs principles. Studying these chemical inducers of proximity in translationally relevant models of prostate cancer, we will provide a blueprint for converting neo-agonistic covalent FOXA1 ligands into FOXA1 antagonists, enabling a first prosecution of this attractive, yet historically challenging, transcription factor drug target.


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 = $744,054 )
2026	2026	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	1	7/20/2026	NEW	$744,054
														Subtotal = $744,054

Grand Total All Awards = $744,054

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Chemical inducers of proximity to antagonize FOXA1

Award Number: R01CA303840

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/20/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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