A hallmark of cancer is the evasion of apoptosis. Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) family of proteins that regulates the mitochondrial apoptosis pathway. Overexpression of MCL-1 contributes to oncogenesis and confers resistance to cancer treatments. Protein-protein interactions (PPI) are constitutive of the dynamic interplay between the pro- and anti-apoptotic proteins of the BCL-2 family, which is integral to controlling the apoptotic threshold of cells. Therapeutic intervention by small molecule BH3 mimetics to pharmacologically target the PPI and antagonize MCL-1 has made significant progress in recent years in oncology with multiple candidates entering clinical trials. This digest accounts the state-of-art MCL-1 inhibitors with emphasis on their discovery medicinal chemistry, highlighted in structure-based drug design (SBDD) and biological evaluations.

癌症的一个标志是逃避细胞凋亡。髓细胞白血病-1 (MCL-1) 是 B 细胞淋巴瘤-2 (BCL-2) 蛋白家族的抗凋亡成员，可调节线粒体凋亡途径。MCL-1 的过度表达有助于肿瘤发生并赋予对癌症治疗的抗性。蛋白质-蛋白质相互作用 (PPI) 是 BCL-2 家族的促凋亡蛋白和抗凋亡蛋白之间动态相互作用的组成部分，这是控制细胞凋亡阈值不可或缺的一部分。近年来，通过小分子 BH3 模拟物在药理学上靶向 PPI 和拮抗 MCL-1 的治疗干预在肿瘤学方面取得了重大进展，多个候选药物进入临床试验。该文摘说明了最先进的 MCL-1 抑制剂，重点是它们的药物化学发现，