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Democratizing Chemical Proteomics: A Platform for Same-Day Photoaffinity Probes to Drive Whole-Proteome Selectivity in Cancer Drug Discovery

Award Number: R61CA317242
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Democratizing Chemical Proteomics: A Platform for Same-Day Photoaffinity Probes to Drive Whole-Proteome Selectivity in Cancer Drug Discovery - Project Summary/Abstract Cancer drug discovery continues to face exceptionally high attrition rates, with nearly 90% of clinical candidates failing due to insufficient efficacy or unacceptable toxicity. A key driver of this attrition is the lack of systematic tools to assess drug selectivity early in development. Current chemoproteomic methods enable proteome-wide mapping only for a limited fraction of drugs: covalent cysteine-reactive probes (~10% of FDA-approved cancer drugs) and amine-based photoaffinity probes (~20%). As a result, the vast majority of drug chemical space and human proteins remain inaccessible to unbiased profiling, leaving off-target toxicities and efficacy boundaries undefined until late clinical stages. This project will develop and validate a first-in-class, synthesis-free, scaffold-agnostic platform for the rapid generation of stochastic photoaffinity probes (St-AfBPs). The core innovation lies in trifunctional diazirine/diaziridine building blocks that allow the same-day conversion of virtually any small molecule into a proteomic probe, eliminating the need for rational probe design and bespoke synthesis. These probes are cell-permeable and capture protein interactions directly in live cells, enabling the construction of structure–proteome selectivity relationships (SPSRs). The research will proceed through three aims: (1) synthesis of five distinct St-AfBP building blocks with varied photochemical properties; (2) establishment of the stochastic photomodification protocol and benchmarking of St-AfBPs against rationally designed probes using diverse FDA-approved cancer drugs; and (3) application of the platform to profile proteome-wide selectivity landscapes across multiple cancer models, including resistant variants, with bioinformatic correlation to known toxicity and efficacy pathways. Completion of these aims will deliver a broadly applicable chemical proteomics technology that democratizes probe generation, expands proteome coverage well beyond current methods, and enables the early identification of drug selectivity liabilities. The long-term impact is to reduce clinical attrition in oncology and accelerate the development of safer, more effective cancer therapeutics.


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 = $147,127 )
2026	2026	ARISTOTELIO PANEPISTIMIO THESSALONIKIS - EIDIKOS LOGARIASMOS KONDILION EREVNAS	TRITIS SEPTEMVRIOU, KEDEA BUILDING	THESSALONIKI				GRC	Cancer Biology Research	001	1	9/17/2026	NEW	$0
2026	2026	ARISTOTELIO PANEPISTIMIO THESSALONIKIS - EIDIKOS LOGARIASMOS KONDILION EREVNAS	TRITIS SEPTEMVRIOU, KEDEA BUILDING	THESSALONIKI				GRC	Cancer Biology Research	000	1	9/16/2026	NEW	$147,127
														Subtotal = $147,127

Grand Total All Awards = $147,127

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Democratizing Chemical Proteomics: A Platform for Same-Day Photoaffinity Probes to Drive Whole-Proteome Selectivity in Cancer Drug Discovery

Award Number: R61CA317242

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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