Discovery and Optimization of a Covalent AKR1C3 Inhibitor

Aldo-keto reductase family 1 member C3 (AKR1C3) is a member of the AKR superfamily of enzymes that metabolize androgen, estrogen, and prostaglandin substrates that drive proliferation in hormone-dependent cancers. Interest in developing selective inhibitors has produced tool compounds for the inactivation or degradation of AKR1C3 with varying degrees of selectivity among the 14 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 selectively engages a noncatalytic tyrosine residue (Y24) on AKR1C3. Importantly, RJG-2051 exhibited negligible cross-reactivity with AKRs or other proteins across 1800+ tyrosine and lysine sites quantified by chemical proteomics. Our disclosure of a covalent inhibitor for potent AKR1C3 inactivation with proteome-wide selectivity in cells will expedite cell biological studies for testing the therapeutic potential of this metabolic target.