Myeloid cell leukemia-1 (MCL-1), a key anti-apoptotic protein within the BCL-2 family, is essential in regulating cell survival, particularly in cancer, where its overexpression is often linked to therapeutic resistance. This review begins with an overview of BCL-2-mediated apoptosis, highlighting the pivotal role of MCL-1 in cellular homeostasis. We then focus on the structure and function of MCL-1, elucidating how its unique structural features contribute to its function and interaction with pro-apoptotic proteins. The core of this review is a detailed structural analysis of selective MCL-1 inhibitors, tracing their development from initial discovery to stepwise optimization. We explore various classes of inhibitors, including those with distinct core structures, covalent inhibitors that reversibly/irreversibly bind to MCL-1, and innovative approaches such as metal-based inhibitors and proteolysis-targeting chimeras (PROTACs). The structural evolution of these inhibitors is discussed, with particular emphasis on the modifications that have enhanced their selectivity, potency, and pharmacokinetic profiles. Additionally, we summarize the synergistic potential of MCL-1 inhibitors when used in combination with other therapeutic agents, emphasizing their role in overcoming drug resistance. The review concludes with a discussion of current challenges in MCL-1 modulation and future perspectives, proposing alternative strategies for targeting this critical protein for cancer therapy.

中文翻译：

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选择性髓系白血病 1 抑制剂的化学解剖：它们是如何被发现和进化的


髓样细胞白血病-1 （MCL-1） 是 BCL-2 家族中的关键抗凋亡蛋白，在调节细胞存活方面至关重要，尤其是在癌症中，其过表达通常与治疗耐药性有关。本文首先概述了 BCL-2 介导的细胞凋亡，强调了 MCL-1 在细胞稳态中的关键作用。然后，我们专注于 MCL-1 的结构和功能，阐明其独特的结构特征如何促进其功能和与促凋亡蛋白的相互作用。本综述的核心是对选择性 MCL-1 抑制剂的详细结构分析，追溯它们从最初发现到逐步优化的发展。我们探索了各种类型的抑制剂，包括具有不同核心结构的抑制剂、与 MCL-1 可逆/不可逆结合的共价抑制剂，以及金属基抑制剂和蛋白水解靶向嵌合体 （PROTAC） 等创新方法。讨论了这些抑制剂的结构演变，特别强调了增强其选择性、效力和药代动力学特征的修饰。此外，我们总结了 MCL-1 抑制剂与其他治疗药物联合使用时的协同潜力，强调了它们在克服耐药性方面的作用。综述最后讨论了 MCL-1 调节的当前挑战和未来前景，提出了靶向这种关键蛋白质进行癌症治疗的替代策略。