Design, synthesis, and biological evaluation of cytochrome P450 CYP11A1 inhibitors

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-06-01 Epub Date: 2026-01-31 DOI:10.1016/j.bmcl.2026.130567

Dongyu Wang , Shengkai Cui , Jingyi Yuan, Yuyang Li, Yujie Zhang, Yuao Zhang, Weizheng Fan, Chunlei Tang

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引用次数: 0

Abstract

This study addresses drug resistance in castration-resistant prostate cancer by developing novel inhibitors of CYP11A1, the key rate-limiting enzyme in androgen synthesis. Based on the clinical candidate Opevesostat, two series of 23 new compounds were designed and synthesized using a 4H-pyran-4-one core to explore structure-activity relationships at the C2 and C6 positions.Compound II-4 exhibited potent inhibitory activity (95.2% at 100 nM; IC₅₀ = 26.7 nM), comparable to Opevesostat (IC₅₀ = 20.4 nM). Importantly, II-4 showed superior selectivity against CYP1A2, 2C9, and 2D6 (2- to 4-fold improvement), attributed to hydrophobic interactions between its C6 methyl group and Ile 84.These results highlight II-4 as a promising lead compound with optimized activity and selectivity, providing valuable insights for overcoming resistance in prostate cancer therapy.

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细胞色素P450 CYP11A1抑制剂的设计、合成和生物学评价。

本研究通过开发新的CYP11A1抑制剂来解决去势抵抗性前列腺癌的耐药性问题，CYP11A1是雄激素合成的关键限速酶。以临床候选药物Opevesostat为基础，以4h -pyran-4- 1为核心，设计并合成了两个系列共23个新化合物，以探索C2和C6位点的构效关系。化合物II-4表现出有效的抑制活性（在100 nM时95.2%;IC₅₀ = 26.7 nM），与Opevesostat （IC₅₀ = 20.4 nM）相当。重要的是，II-4对CYP1A2、2C9和2D6表现出优异的选择性（提高了2- 4倍），这归因于其C6甲基与Ile 84之间的疏水相互作用。这些结果突出了II-4作为一种具有优化活性和选择性的先导化合物，为克服前列腺癌治疗的耐药提供了有价值的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.