Therapeutics targeting BCL2 family proteins

BCL2 family proteins play an essential role in controlling mitochondrial outer membrane permeabilization which is the fatal and usually irreversible step of the mitochondrial apoptotic pathway. Moreover, BCL2 family proteins are also involved in the regulations of other cellular processes, such as autophagy, mitochondrial fission and fusion, and endoplasmic reticulum stress. Three proteins, BAK, BAX, and BOK, are the effector BCL2 family proteins that directly permeabilize the mitochondrial outer membrane while the antiapoptotic BCL2 family members and the BH3-only subfamily proteins regulate this process through protein–protein interactions. BCL2 family proteins are known to be important in the development of several diseases, especially cancer. Thus, much effort has gone into the development of drugs targeting BCL2 family proteins to treat cancer; developed agents include antisense oligonucleotides, modified peptides, and small molecules. Some of these efforts have been quite successful, with several candidates tested in clinical trials. Moreover, ABT-199 (venetoclax) was approved by the United States Food and Drug Administration to treat relapsed, chromosome 17p-deleted chronic lymphocytic leukemia in 2016, providing a huge inspiration for this field. In this chapter, we summarize the recent advances in BCL2 family studies, review the latest developments and clinical studies of drug candidates to target BCL2 family proteins, and discuss future directions of this class of antineoplastic agents.