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