Identification of the Highly Active, Species Cross-Reactive Complex I Inhibitor BAY-179,ACS Medicinal Chemistry Letters

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Identification of the Highly Active, Species Cross-Reactive Complex I Inhibitor BAY-179
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2022-02-18 , DOI: 10.1021/acsmedchemlett.1c00666
Jeffrey Mowat ₁ , Alexander H M Ehrmann ₂ , Sven Christian ₁ , Carolyn Sperl ₁ , Stephan Menz ₁ , Judith Günther ₁ , Roman C Hillig ₁ , Marcus Bauser ₁ , Wolfgang Schwede ₁

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Mitochondria are key regulators of energy supply and cell death. Generation of ATP within mitochondria occurs through oxidative phosphorylation (OXPHOS), a process which utilizes the four complexes (complex I–IV) of the electron transport chain and ATP synthase. Certain oncogenic mutations (e.g., LKB1 or mIDH) can further enhance the reliance of cancer cells on OXPHOS for their energetic requirements, rendering cells sensitive to complex I inhibition and highlighting the potential value of complex I as a therapeutic target. Herein, we describe the discovery of a potent, selective, and species cross-reactive complex I inhibitor. A high-throughput screen of the Bayer compound library followed by hit triaging and initial hit-to-lead activities led to a lead structure which was further optimized in a comprehensive lead optimization campaign. Focusing on balancing potency and metabolic stability, this program resulted in the identification of BAY-179, an excellent in vivo suitable tool with which to probe the biological relevance of complex I inhibition in cancer indications.

中文翻译：

高活性物种交叉反应复合物 I 抑制剂 BAY-179 的鉴定

线粒体是能量供应和细胞死亡的关键调节剂。线粒体中 ATP 的产生通过氧化磷酸化 (OXPHOS) 发生，该过程利用电子传递链和 ATP 合酶的四种复合物（复合物 I-IV）。某些致癌突变（例如, LKB1 或 mIDH) 可以进一步增强癌细胞对其能量需求的 OXPHOS 依赖，使细胞对复合物 I 抑制敏感，并突出复合物 I 作为治疗靶点的潜在价值。在此，我们描述了一种有效的、选择性的和物种交叉反应的复合物 I 抑制剂的发现。拜耳化合物库的高通量筛选，然后是命中分类和初始命中到先导活动，导致先导结构在综合先导优化活动中进一步优化。该项目专注于平衡效力和代谢稳定性，最终鉴定出 BAY-179，这是一种出色的体内适用工具，可用于探索复合物 I 抑制在癌症适应症中的生物学相关性。

更新日期：2022-02-18

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