Selective targeting of antiapoptotic BCL‐2 proteins in cancer

Circumvention of apoptotic machinery is one of the distinctive properties of carcinogenesis. Extensively established key effectors of such apoptotic bypass mechanisms, the antiapoptotic BCL‐2 (apoptosis regulator BCL‐2) proteins, determine the response of cancer cells to chemotherapeutics. Within this background, research and development of antiapoptotic BCL‐2 inhibitors were considered to have a tremendous amount of potential toward the discovery of novel pharmacological modulators in cancer. In this review, milestone achievements in the development of selective antiapoptotic BCL‐2 proteins inhibitors for BCL‐2, BCL‐XL (BCL‐2‐like protein 1), and MCL‐1 (induced myeloid leukemia cell differentiation protein MCL‐1) were summarized and their future implications were discussed. In the first section, the design and development of BCL‐2/BCL‐XL dual inhibitor navitoclax, as well as the recent advances and clinical experience with selective BCL‐2 inhibitor venetoclax, were synopsized. Preclinical data from selective BCL‐XL inhibitors, which are currently undergoing extensive testing as a single agent or in combination with other therapeutic agents, were further summarized. In the second section, MCL‐1 inhibitors developed as potential anticancer agents were reviewed regarding their specificity toward MCL‐1. Explicitly, studies leading to the identification of MCL‐1, nonselective and selective targeting of MCL‐1, and recently initiated clinical trials were compiled in chronological order. Based on these concepts, future directions were further discussed for increasing selectivity in the design of prosurvival BCL‐2 member inhibitors.