Toward Targeting Antiapoptotic MCL-1 for Cancer Therapy

Abstract

Apoptosis is critical for embryonic development, tissue homeostasis, and the removal of infected or otherwise dangerous cells. It is controlled by three subgroups of the BCL-2 protein family—the BH3-only proteins that initiate cell death; the effectors of cell killing, BAX and BAK; and the antiapoptotic guardians, including MCL-1 and BCL-2. Defects in apoptosis can promote tumorigenesis and render malignant cells refractory to anticancer therapeutics. Activation of cell death by inhibiting antiapoptotic BCL-2 family members has emerged as an attractive strategy for cancer therapy, with the BCL-2 inhibitor venetoclax leading the way. Large-scale cancer genome analyses have revealed frequent amplification of the locus encoding antiapoptotic MCL-1 in human cancers, and functional studies have shown that MCL-1 is essential for the sustained survival and expansion of many types of tumor cells. Structural analysis and medicinal chemistry have led to the development of three distinct small-molecule inhibitors of MCL-1 that are currently undergoing clinical testing.