2. Academic Validation
  3. Small-molecule allosteric inhibitors of BAX

Small-molecule allosteric inhibitors of BAX

  • Nat Chem Biol. 2019 Apr;15(4):322-330. doi: 10.1038/s41589-018-0223-0.
Thomas P Garner 1 2 3 4,  Dulguun Amgalan 2 3 4 5,  Denis E Reyna 1 2 3 4,  Sheng Li 6,  Richard N Kitsis 2 3 4 5,  Evripidis Gavathiotis 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 2 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 3 Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 4 Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 5 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 6 Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • 7 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einstein.yu.edu.
  • 8 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einstein.yu.edu.
  • 9 Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einstein.yu.edu.
  • 10 Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA. evripidis.gavathiotis@einstein.yu.edu.
PMID: 30718816 DOI: 10.1038/s41589-018-0223-0
Abstract

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 α5 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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