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Targeting BAX to drug death directly

Nature Chemical Biology volume 15, pages 657–665 (2019)Cite this article

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Abstract

BCL-2 family protein interactions regulate apoptosis, a critical process that maintains tissue homeostasis but can cause a host of human diseases when deregulated. Venetoclax is the first FDA-approved drug to reactivate apoptosis in cancer by selectively targeting an anti-apoptotic BCL-2 family member. The drug’s activity relies on an ‘inhibit the inhibitor’ mechanism, whereby blockade of a key surface groove on BCL-2 disables its capacity to neutralize pro-apoptotic effectors, such as BAX, a chief executioner protein of the apoptotic pathway. A series of physiologic and pharmacologic regulatory sites that mediate the activation or inhibition of BAX have recently been identified, providing blueprints for the development of alternative apoptosis modulators to block pathologic cell survival or avert unwanted cell death by drugging BAX directly.

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Fig. 1: BAX and BCL-2: wrestling twins that regulate apoptosis during homeostasis and disease.
Fig. 2: Indirect and direct activation of BAX-mediated apoptosis.
Fig. 3: A BH3 trigger site mediates the direct activation of BAX.
Fig. 4: Mechanistic basis for a therapeutic window for indirect and direct pharmacologic activation of BAX.
Fig. 5: Molecular and mechanistic diversity of BAX sensitizers and activators.
Fig. 6: Modulating apoptosis by direct targeting of the canonical pocket of BAK.
Fig. 7: Physiologic inhibitors of BAX restrain key structural regions implicated in BAX activation.
Fig. 8: Small-molecule inhibition of BAX.

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Acknowledgements

The author would like to thank E. Smith for figure preparation and graphics support. This work was supported by National Institutes of Health (NIH) grant R35CA197583 and a Leukemia and Lymphoma Society (LLS) Scholar Award. The author is also indebted to the Wolpoff Family Foundation, J. and L. LaTorre, the family of I. Coll, and the Todd J. Schwartz Memorial Fund for their steadfast financial contributions to our cancer chemical biology research.

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  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Loren D. Walensky

  2. Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Loren D. Walensky

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Correspondence to Loren D. Walensky.

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L.D.W. is a scientific advisory board member and consultant for Aileron Therapeutics.

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Walensky, L.D. Targeting BAX to drug death directly. Nat Chem Biol 15, 657–665 (2019). https://doi.org/10.1038/s41589-019-0306-6

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