Journal
NATURE CHEMICAL BIOLOGY
Volume 15, Issue 4, Pages 322-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-018-0223-0
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Funding
- American Heart Association Collaborative Science Award [15CSA26240000]
- NIH [1R01CA178394]
- Fondation Leducq Transatlantic Network of Excellence grant [RA15CVD04]
- Pershing Square Sohn Cancer Research Alliance
- Irma T. Hirschl Trust Career Award
- NIH from NYSTAR [1S10OD016305, P30 CA013330]
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BAX is a critical effector of the mitochondrial cell death pathway in response to a diverse range of stimuli in physiological and disease contexts. Upon binding by BH3-only proteins, cytosolic BAX undergoes conformational activation and translocation, resulting in mitochondrial outer-membrane permeabilization. Efforts to rationally target BAX and develop inhibitors have been elusive, despite the clear therapeutic potential of inhibiting BAX-mediated cell death in a host of diseases. Here, we describe a class of small-molecule BAX inhibitors, termed BAIs, that bind directly to a previously unrecognized pocket and allosterically inhibit BAX activation. BAI binding around the hydrophobic helix alpha 5 using hydrophobic and hydrogen bonding interactions stabilizes key areas of the hydrophobic core. BAIs inhibit conformational events in BAX activation that prevent BAX mitochondrial translocation and oligomerization. Our data highlight a novel paradigm for effective and selective pharmacological targeting of BAX to enable rational development of inhibitors of BAX-mediated cell death.
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