Mowat Jeffrey, Ehrmann Alexander H M, Christian Sven, Sperl Carolyn, Menz Stephan, Günther Judith, Hillig Roman C, Bauser Marcus, Schwede Wolfgang
Pharmaceuticals R&D, Bayer AG, 13342 Berlin, Germany.
Pharmaceuticals R&D, Bayer AG, 42113 Wuppertal, Germany.
ACS Med Chem Lett. 2022 Feb 18;13(3):348-357. doi: 10.1021/acsmedchemlett.1c00666. eCollection 2022 Mar 10.
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 (, 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 suitable tool with which to probe the biological relevance of complex I inhibition in cancer indications.
线粒体是能量供应和细胞死亡的关键调节因子。线粒体中ATP的生成通过氧化磷酸化（OXPHOS）进行，这一过程利用电子传递链的四种复合物（复合物I-IV）和ATP合酶。某些致癌突变（如LKB1或mIDH）可进一步增强癌细胞对OXPHOS以满足其能量需求的依赖性，使细胞对复合物I抑制敏感，并突出了复合物I作为治疗靶点的潜在价值。在此，我们描述了一种强效、选择性且具有物种交叉反应性的复合物I抑制剂的发现。对拜耳化合物库进行高通量筛选，随后进行命中物筛选和初步的从命中物到先导物的活性研究，得到了一个先导结构，该结构在全面的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，这是一种优秀的合适工具，可用于探究复合物I抑制在癌症适应症中的生物学相关性。
