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BH3 mimetics act by inhibiting the prosurvival BCL2 proteins to enable the activation of BAX and BAK, apoptosis effectors that permeabilize the outer mitochondrial membrane, triggering apoptosis directly in many cells and sensitizing others to cell death when combined with other antineoplastic drugs. Venetoclax, a specific inhibitor of BCL2, is the first approved in class, demonstrating striking single agent activity in chronic lymphocytic leukemia and in other lymphoid neoplasms, as well as activity against acute myeloid leukemia (AML), especially when used in combination. Key insights from the venetoclax experience include that responses occur rapidly, with major activity as monotherapy proving to be the best indicator for success in combination regimens. This emphasizes the importance of adequate single-agent studies for drugs in this class. Furthermore, secondary resistance is common with long-term exposure and often mediated by genetic or adaptive changes in the apoptotic pathway, suggesting that BH3 mimetics are better suited to limited duration, rather than continuous, therapy. The success of venetoclax has inspired development of BH3 mimetics targeting MCL1. Despite promising preclinical activity against MYC-driven lymphomas, myeloma, and AML, their success may particularly depend on their tolerability profile given physiological roles for MCL1 in several nonhematologic tissues.<\/jats:p>","DOI":"10.1182\/blood.2020006785","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T13:55:20Z","timestamp":1627480520000},"page":"1120-1136","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":197,"title":["BCL2 and MCL1 inhibitors for hematologic malignancies"],"prefix":"10.1182","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7341-5720","authenticated-orcid":false,"given":"Andrew W.","family":"Roberts","sequence":"first","affiliation":[{"name":"Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;"},{"name":"Department of Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;"},{"name":"Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia;"},{"name":"Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7514-3298","authenticated-orcid":false,"given":"Andrew H.","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia; and"},{"name":"Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3101-4873","authenticated-orcid":false,"given":"David C. 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