The MCL1-specific inhibitor S63845 acts synergistically with venetoclax/ABT-199 to induce apoptosis in T-cell acute lymphoblastic leukemia cells

The mitochondrial cell death pathway is initiated by pro-apoptotic BH3-only effector proteins, such as BIM, BID, NOXA, and PUMA, which activate the multidomain cell death proteins, BAX and BAK [ 1 ]. The survival of tumor cells, as well as normal cells, is promoted by anti-apoptotic BCL-2-family members, including BCL-2, BCL-X L , and MCL1, which bind and sequester BH3-only proteins, thus preventing them from activating BAX and BAK [ 1 ]. Cancer cells tend to rely more heavily on anti-apoptotic BCL-2 family proteins because of replicative and other stresses that accompany malignant transformation, and thus are “primed” to undergo apoptosis more readily than normal cells [ 1 ]. Small molecules have been developed that mimic the BH3 domain and block binding of endogenous BH3 proteins to a groove on the surface of one or more of the pro-survival proteins. Promising examples are navitoclax/ABT-263, targeting BCL-2, BCL-X L , and BCL-W, and more recently venetoclax/ABT-199 targeting BCL-2 alone [ 2 ]. The most successful of these drugs is the BCL-2 inhibitor venetoclax, which is approved for the treatment of chronic lymphocytic leukemia (CLL) [ 2 , 3 ] and has shown considerable activity in therapy for other cancers, such as acute myeloid leukemia (AML) [ 4 ]. Venetoclax is better tolerated than navitoclax, because it does not bind to BCL-X L , which is required for the survival of normal platelets [ 3 ].