https://orcid.org/0000-0002-8980-2338
Figures & data
Figure 1 BCL-2 family protein interactions. DNA damage and cellular stress such as that caused by DNA damaging agents or proteosome inhibitors induce the expression of apoptotic sensitizers HRK, BAD, NOXA, BMF, and BIK (not pictured). These proteins selectively bind to and inhibit the anti-apoptotic BCL2 family members BCLXL BCL2, BCLW, MCL1, and BFL1. Anti-apoptotic BCL2 family proteins sequester apoptotic activator proteins PUMA, tBID, and BIM. Free apoptotic activators induce the oligomerization of apoptotic effectors BAK and BAX at the mitochondrial membrane. BAK and BAX oligomerization causes mitochondrial outer membrane permeabilization and the release of cytochrome C into the cytosol resulting in apoptosome formation and caspase activation.
Figure 2 BCL-2 Family inhibitors and their targets. Venetoclax (ABT-199) is a BCL2 selective inhibitor and approved for use in CLL, SLL, and AML under the trade name VENCLEXTA®. ABT-737 inhibits BCL2, BCLXL, and BCLW (not shown). Similar to ABT-737, Navitoclax inhibits BCL-2, BCLXL, and BCLW but is orally bioavailable. A-1155463 and A-1331852 are selective BCLXL inhibitors. There are five selective MCL1 inhibitors in early clinical trials: S64315 (MIK665), AZD5991, AMG176, AMG379, and ABBV467.
Table 1 Venetoclax Toxicities
Table 2 Previous Therapy and Responses in Venetoclax Trials
Table 3 Currently Open Clinical Trials Investigating BCL2 Family Inhibitors