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From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors

From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors Members of the B cell lymphoma 2 (BCL-2) gene family have a key role in regulating programmed cell death by controlling pro-apoptotic and anti-apoptotic intracellular signals. Augmentation of anti-apoptotic signalling is a hallmark of cancer; inhibition of specific anti-apoptotic BCL-2 proteins represents an important novel therapeutic strategy. The first bona fide BCL-2 homology 3 (BH3) mimetics — compounds that are capable of potently and specifically disrupting interactions between anti-apoptotic and pro-apoptotic BCL-2 family proteins — have been developed using a combination of nuclear magnetic resonance-based screening, fragment chemistry and structure-based drug design. Navitoclax, a dual antagonist of BCL-2 and BCL-XL, was the first BCL-2 inhibitor to show efficacy in cancer; however, the use of this drug was limited by the occurrence of neutropenia. The highly selective and potent BCL-2 inhibitor venetoclax was subsequently developed and is now approved in the United States for the treatment of relapsed or refractory chronic lymphocytic leukaemias that have a deletion of the 17p13 chromosomal region. Recent advances have also been made in the development of inhibitors that specifically target BCL-XL and myeloid cell leukaemia 1 (MCL1), which are additional BCL-2 family members that have demonstrated roles in cancer. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Drug Discovery Springer Journals

From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors

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References (113)

Publisher
Springer Journals
Copyright
Copyright © 2017 by Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
Subject
Biomedicine; Biomedicine, general; Pharmacology/Toxicology; Biotechnology; Medicinal Chemistry; Molecular Medicine; Cancer Research
ISSN
1474-1776
eISSN
1474-1784
DOI
10.1038/nrd.2016.253
Publisher site
See Article on Publisher Site

Abstract

Members of the B cell lymphoma 2 (BCL-2) gene family have a key role in regulating programmed cell death by controlling pro-apoptotic and anti-apoptotic intracellular signals. Augmentation of anti-apoptotic signalling is a hallmark of cancer; inhibition of specific anti-apoptotic BCL-2 proteins represents an important novel therapeutic strategy. The first bona fide BCL-2 homology 3 (BH3) mimetics — compounds that are capable of potently and specifically disrupting interactions between anti-apoptotic and pro-apoptotic BCL-2 family proteins — have been developed using a combination of nuclear magnetic resonance-based screening, fragment chemistry and structure-based drug design. Navitoclax, a dual antagonist of BCL-2 and BCL-XL, was the first BCL-2 inhibitor to show efficacy in cancer; however, the use of this drug was limited by the occurrence of neutropenia. The highly selective and potent BCL-2 inhibitor venetoclax was subsequently developed and is now approved in the United States for the treatment of relapsed or refractory chronic lymphocytic leukaemias that have a deletion of the 17p13 chromosomal region. Recent advances have also been made in the development of inhibitors that specifically target BCL-XL and myeloid cell leukaemia 1 (MCL1), which are additional BCL-2 family members that have demonstrated roles in cancer.

Journal

Nature Reviews Drug DiscoverySpringer Journals

Published: Feb 17, 2017

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