Abstract 4497: Discovery and optimization of a covalent AKR1C3 inhibitor for evaluation in hormone-dependent cancers

Aldo-keto reductase family 1 member C3 (AKR1C3) is a member of the AKR superfamily of enzymes that metabolizes androgen, estrogen, and prostaglandin substrates to produce potent drivers of proliferation in hormone-dependent cancers. Interest in developing selective inhibitors have produced tool compounds for inactivation or degradation of AKR1C3 with varying degrees of selectivity among the 15 known AKR proteins. Selectivity of AKR1C3 inhibitors across the AKR family is critical since a clinical candidate failed due to hepatotoxicity from off-target inhibition of AKR1D1. Here, we report development of a sulfonyl-triazole (SuTEx) covalent AKR1C3 inhibitor (RJG-2051) that site selectively engages a non-catalytic tyrosine residue on AKR1C3 in cells. Importantly, RJG-2051 exhibited negligible cross-reactivity with detectable AKRs or other proteins across thousands of tyrosine and lysine sites quantified by chemical proteomics. The disclosure of a covalent and proteome-wide selective inhibitor for potent AKR1C3 inactivation in cells will expedite cell biological studies for testing the therapeutic potential of this metabolic target. Citation Format: Robert J. Grams, Robert J. Seal, James Veccia, Ku-Lung Hsu. Discovery and optimization of a covalent AKR1C3 inhibitor for evaluation in hormone-dependent cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4497.