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.

醛酮还原酶家族1成员C3（Aldo-keto reductase family 1 member C3，AKR1C3）是AKR酶超家族的一员，该超家族的酶可代谢雄激素、雌激素以及在激素依赖性癌症中驱动细胞增殖的前列腺素底物。学界针对选择性抑制剂开发所开展的研究，已获得可灭活或降解AKR1C3的工具化合物，这类化合物在已鉴定的14种AKR蛋白中选择性各不相同。AKR1C3抑制剂在整个AKR家族中的选择性至关重要，因为曾有一款临床候选药物因脱靶抑制AKR1D1引发肝毒性而研发失败。本研究报道了一种磺酰基三唑（sulfonyl-triazole，SuTEx）类共价AKR1C3抑制剂RJG-2051，该化合物可选择性结合AKR1C3上的一个非催化酪氨酸残基Y24。值得注意的是，通过化学蛋白质组学（chemical proteomics）定量分析的1800余个酪氨酸、赖氨酸位点中，RJG-2051与其他AKR家族蛋白及其他蛋白几乎无交叉反应性。本研究公开了一种可强效灭活AKR1C3且在细胞内具有蛋白质组范围选择性的共价抑制剂，这将加速相关细胞生物学研究，以验证这一代谢靶点的治疗潜力。