2. Academic Validation
  3. Covalent inhibition of pro-apoptotic BAX

Covalent inhibition of pro-apoptotic BAX

  • Nat Chem Biol. 2024 Jan 17. doi: 10.1038/s41589-023-01537-6.
Matthew W McHenry 1 2,  Peiwen Shi 1,  Christina M Camara 1,  Daniel T Cohen 1,  T Justin Rettenmaier 3,  Utsarga Adhikary 1,  Micah A Gygi 1,  Ka Yang 4,  Steven P Gygi 4,  Thomas E Wales 5,  John R Engen 5,  James A Wells 3,  Loren D Walensky 6
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology and Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
  • 3 Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
  • 4 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.
  • 6 Department of Pediatric Oncology and Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA. loren_walensky@dfci.harvard.edu.
PMID: 38233584 DOI: 10.1038/s41589-023-01537-6
Abstract

BCL-2-associated X protein (Bax) is a promising therapeutic target for activating or restraining Apoptosis in diseases of pathologic cell survival or cell death, respectively. In response to cellular stress, Bax transforms from a quiescent cytosolic monomer into a toxic oligomer that permeabilizes the mitochondria, releasing key apoptogenic factors. The mitochondrial lipid trans-2-hexadecenal (t-2-hex) sensitizes Bax activation by covalent derivatization of cysteine 126 (C126). In this study, we performed a disulfide tethering screen to discover C126-reactive molecules that modulate Bax activity. We identified covalent Bax Inhibitor 1 (CBI1) as a compound that selectively derivatizes Bax at C126 and inhibits Bax activation by triggering ligands or point mutagenesis. Biochemical and structural analyses revealed that CBI1 can inhibit Bax by a dual mechanism of action: conformational constraint and competitive blockade of lipidation. These data inform a pharmacologic strategy for suppressing Apoptosis in diseases of unwanted cell death by covalent targeting of Bax C126.

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