MCL-1 is a member of the BCL-2 family of proteins that regulates the mitochondrial pathway of apoptosis. Overexpression of MCL-1 is associated with the development and progression of a range of human cancers, and is also responsible for the onset of resistance to conventional chemotherapies. Although several MCL-1 inhibitors have now advanced to clinical trials, recent suspensions and terminations reveal the urgency with which new inhibitor chemotypes must be discovered. Building on our previous studies of a chiral, isomeric lead, we report the discovery of a new chemotype to inhibit MCL-1: 1-sulfonylated 1,2,3,4-tetrahydroquinoline-6-carboxylic acid. The nature of the sulfonyl moiety contributed significantly to the resulting inhibitory ability. For example, transforming a phenylsulfonyl group into a 4-chloro-3,5-dimethylphenoxy)phenyl)sulfonyl moiety elicited more than a 73-fold enhancement in inhibiton of MCL-1, possibly through targeting the p2 pocket in the BH3-binding groove, and so it is anticipated that further structure-activity studies here will lead to continued improvements in binding. It should be underscored that this class of MCL-1 inhibitors is readily accessible in four simple steps, is achiral and offers many avenues for optimization, all factors that are welcomed in the search for safe and effective inhibitors of this driver of cancer cell survival.

中文翻译：

---

1-磺酰化 1,2,3,4-四氢喹啉-6-羧酸作为简单易得的 MCL-1 抑制剂

MCL-1 是 BCL-2 蛋白家族的成员，可调节细胞凋亡的线粒体途径。MCL-1 的过度表达与一系列人类癌症的发生和发展有关，也是对传统化疗产生耐药性的原因。尽管几种 MCL-1 抑制剂现已进入临床试验，但最近的暂停和终止表明必须发现新的抑制剂化学型的紧迫性。基于我们之前对手性异构先导化合物的研究，我们报告了一种抑制 MCL-1 的新化学型的发现：1-磺酰化 1,2,3,4-四氢喹啉-6-羧酸。磺酰基部分的性质对产生的抑制能力有显着影响。例如，将苯磺酰基转化为 4-chloro-3，5-二甲基苯氧基）苯基）磺酰基部分引起超过 73 倍的 MCL-1 抑制增强，可能是通过靶向 BH3 结合沟中的 p2 袋，因此预计这里的进一步结构活性研究将导致继续改进绑定。应该强调的是，这类 MCL-1 抑制剂很容易通过四个简单的步骤获得，是非手性的，并提供许多优化途径，所有这些因素在寻找这种癌细胞存活驱动因素的安全有效抑制剂时受到欢迎。