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Signal transduction, cell biology and molecular pharmacology of ectopically expressed olfactory GPCR OR51E1

Award Number: R01CA296645
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/02/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Signal transduction, cell biology and molecular pharmacology of ectopically expressed olfactory GPCR OR51E1 - G protein-coupled receptors (GPCRs) regulate a vast array of cellular functions through complex signaling networks involving multiple G proteins, downstream effectors, and regulatory molecules. Owing to their central role in maintaining physiological balance, GPCRs constitute one of the most therapeutically significant protein families, with over 30% of all approved drugs targeting them. Olfactory receptors (ORs) are the vast family, comprising about half of the ~800 human GPCRs. Initially identified in the nasal epithelium, ORs have since been found in many tissues, including brain, blood vessels, the gastrointestinal and prostate epithelium. Their roles remain poorly understood, but emerging evidence links specific ORs to pathological conditions. The overarching goal of this project is to fill the knowledge gap surrounding ectopically expressed ORs and to explore their therapeutic potential. We focus on OR51E1, a well-established marker in prostate cancer. OR51E1 has been deorphanized and is activated by butyric acid with an EC₅₀ of ~1 mM (i.e., 10-3M). While the availability of butyrate as an agonist enabled initial functional studies, the low potency and lack of specificity of this generic metabolite significantly limit its utility for investigating OR51E1. Having overcome long-standing technical obstacles that hindered large-scale in vitro expression of functional olfactory receptors, we developed a high-throughput screening (HTS) platform for ORs. Implementation of this HTS, followed by a computational hit expansion screen, led us to the identification of over 100 novel OR51E1 small-molecule agonists (200–400 Da). Several of these compounds show strong selectivity for OR51E1 and are 100–1000 times more potent than butyrate. We also identified approximately five antagonists. Application of the new agonists has, for the first time, revealed a causal relationship between OR51E1 activity and cancer-related cell behaviors, including motility and proliferation. Extending from this success, Aim 1 will investigate prostate cancer cell behaviors, including OR51E1 agonist-stimulated colony formation, increased invasiveness, and changes in downstream gene expression. Aim 2 will elucidate the signaling mechanisms underlying these effects and evaluate the functional relevance of OR51E1’s unique subcellular localization. Aim 3 will refine structure–activity relationship (SAR) insights for OR51E1 antagonists and carry out initial in vivo studies. Achieving these objectives will not only open a new frontier in GPCR signaling and function but also yield tangible molecular tools that bridge basic receptor biology and the future development of targeted therapies.


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 = $606,219 )
2026	2026	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	000	1	7/6/2026	NEW	$606,219
														Subtotal = $606,219

Grand Total All Awards = $606,219

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Signal transduction, cell biology and molecular pharmacology of ectopically expressed olfactory GPCR OR51E1

Award Number: R01CA296645

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/02/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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