Development of Mcl-1 inhibitors for cancer therapy

The myeloid leukemia cell differentiation protein (Mcl-1) is an anti-apoptotic protein of the B-cell lymphoma 2 (Bcl-2) family, which regulates cellular apoptosis. Mcl-1 expression plays a key role in survival of cancer cells and therefore serves as a promising target in cancer therapy. Besides, its importance as a cancer target, various peptides and small-molecule inhibitors have been successfully designed and synthesized, yet no Mcl-1 inhibitor is approved for clinical use. However, recent development on the understanding of Mcl-1's role in key cellular processes in cancer and an upsurge of reports highlighting its association in various anticancer drug resistance supports the view that Mcl-1 is a key target in various cancers, especially hematological cancers. This review compiles structures of a variety of inhibitors of Mcl-1 reported to date. These include inhibitors based on a diverse range of heterocycles (e.g. indole, imidazole, thiophene, nicotinic acid, piperazine, triazine, thiazole, isoindoline), oligomers (terphenyl, quaterpyridine), polyphenol, phenalene, anthranilic acid, anthraquinone, macrocycles, natural products, and metal-based complexes. In addition, an effort has been made to summarize the structure activity relationships, based on a variety of assays, of some important classes of Mcl-1 inhibitors, giving affinities and selectivities for Mcl-1 compared to other Bcl-2 family members. A focus has been placed on categorizing the inhibitors based on their core frameworks (scaffolds) to appeal to the chemical biologist or medicinal chemist. (C) 2020 The Authors. Published by Elsevier Masson SAS.