Chemical dissection of selective myeloid leukemia-1 inhibitors: How they were found and evolved.

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.