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Trends Cancer. 2016 Aug;2(8):443-460. doi: 10.1016/j.trecan.2016.07.001. Epub 2016 Jul 30.

Targeting BCL-2-like Proteins to Kill Cancer Cells.

Author information

1
The Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Victoria 3052, Australia. Electronic address: cory@wehi.edu.au.
2
The Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Victoria 3052, Australia; Department of Clinical Hematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Victoria 3050, Australia; Victorian Comprehensive Cancer Centre, 300 Grattan Street, Parkville, Victoria 3050, Australia.
3
The Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Victoria 3052, Australia.

Abstract

Mutations that impair apoptosis contribute to cancer development and reduce the effectiveness of conventional anti-cancer therapies. These insights and understanding of how the B cell lymphoma (BCL)-2 protein family governs apoptosis have galvanized the search for a new class of cancer drugs that target its pro-survival members by mimicking their natural antagonists, the BCL-2 homology (BH)3-only proteins. Successful initial clinical trials of the BH3 mimetic venetoclax/ABT-199, specific for BCL-2, have led to its recent licensing for refractory chronic lymphocytic leukemia and to multiple ongoing trials for other malignancies. Moreover, preclinical studies herald the potential of emerging BH3 mimetics targeting other BCL-2 pro-survival members, particularly myeloid cell leukemia (MCL)-1, for multiple cancer types. Thus, BH3 mimetics seem destined to become powerful new weapons in the arsenal against cancer. This review sketches the discovery of the BCL-2 family and its impact on cancer development and therapy; describes how interactions of family members trigger apoptosis; outlines the development of BH3 mimetic drugs; and discusses their potential to advance cancer therapy.

KEYWORDS:

BCL-2 protein family; BH3 mimetic drugs; apoptosis; chronic lymphocytic leukemia; drug development; mitochondrial membrane

PMID:
28741496
DOI:
10.1016/j.trecan.2016.07.001
[Indexed for MEDLINE]

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