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

Key Points

  • 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.

Abstract

Members of the B cell lymphoma 2 (BCL-2) gene family have a central role in regulating programmed cell death by controlling pro-apoptotic and anti-apoptotic intracellular signals. In cancer, apoptosis evasion through dysregulation of specific BCL-2 family genes is a recurring event; accordingly, selective inhibition of specific anti-apoptotic BCL-2 family proteins represents an exciting therapeutic opportunity. A combination of nuclear magnetic resonance (NMR)-based screening and structure-based drug design has yielded the first bona fide BCL-2 homology 3 (BH3) mimetics, including the BCL-2 and BCL-XL dual antagonist navitoclax, which is the first BCL-2 family inhibitor to show efficacy in patients with cancer. Clinical experience with navitoclax prompted the generation of the highly selective BCL-2 inhibitor venetoclax, which is now approved in the United States for the treatment of patients with chronic lymphocytic leukaemia with 17p deletion who have received at least one prior therapy. Recent advances have also been made in the development of potent and selective inhibitors of BCL-XL and myeloid cell leukaemia 1 (MCL1), which are additional BCL-2 family members with established anti-apoptotic roles in cancer. Here we review the latest progress in direct and selective targeting of BCL-2 family proteins for cancer therapy.

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Figure 1: The intrinsic apoptosis pathway.
Figure 2: X-ray co-crystal structure of a B cell lymphoma XL molecule complexed with a BCL-2-interacting mediator of cell death peptide.
Figure 3: X-ray co-crystal structure of navitoclax bound to B cell lymphoma XL.
Figure 4: Structures of compounds listed in Table 1.

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Acknowledgements

Under the direction of the authors, editorial assistance was provided by T. N. Miller of Envision Scientific Solutions. T. N. Miller was funded by F. Hoffmann-La Roche.

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Correspondence to Avi Ashkenazi.

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Competing interests

A.A. and W.J.F. are employees of Genentech, South San Francisco, California, USA. A.A. is also an adjunct professor at the University of California San Francisco, USA. J.D.L. and A.J.S. are employees of AbbVie, North Chicago, Illinois, USA.

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Glossary

BH3 mimetics

Small molecules or modified peptides that mimic the action of B cell lymphoma 2 homology 3 (BH3)-only proteins, which insert their BH3 motifs into the hydrophobic groove of the anti-apoptotic B cell lymphoma 2 proteins and inhibit their functional activity, thereby inducing apoptosis.

Alanine scanning mutagenesis

The individual and systematic replacement of amino acids with alanine as a means of assessing the impact of each amino acid on the binding energy of a protein–protein interaction.

Hotspots

Groups of amino acids that make a major contribution to the binding energy of a protein–protein interaction.

Pharmacophore

The collective molecular features of a molecule that define the requirements for binding to a biological target and triggering a biological response.

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Ashkenazi, A., Fairbrother, W., Leverson, J. et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov 16, 273–284 (2017). https://doi.org/10.1038/nrd.2016.253

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