Peiwen Shi, Bruno Melillo, Matthew W. McHenry, Christina M. Camara, Ka Yang, Evert Njomen, Marina Godes, Maria F. Pazyra-Murphy, Mary Rose Branch, Bethany Tesar, Rosalind A. Segal, Lee L. Rubin, Michael D. Cameron, Gregory H. Bird, Thomas E. Wales, Steven P. Gygi, Benjamin F. Cravatt, and Loren D. Walensky.
Nat Chem Biol (2026).
https://doi.org/10.1038/s41589-026-02297-9
No therapies directly block apoptosis in tissue injury or the many diseases driven by cell loss. The BCL-2 family protein BAX is a central mediator of this pathway and C126 resides within a key regulatory region where physiologic or pharmacologic ligands can activate or inhibit its function. Here, we report enantioselective covalent BAX inhibitors that site-specifically react with C126 and confer cytoprotection across multiple cell types. These ligands constrain BAX conformation and suppress apoptosis in a strictly BAX-dependent manner. Medicinal chemistry optimization yielded covalent BAX inhibitor 3 (CBI-3), an analog with pharmacokinetics suitable for in vivo studies. In a murine model of Fas-induced fulminant hepatic failure, CBI-3 reduced hepatocyte apoptosis and preserved liver histology and survival. CBI-3 also conferred cytoprotection of motor neurons derived from human induced pluripotent stem cells of healthy and amyotrophic lateral sclerosis donors. These findings establish covalent BAX inhibition as a therapeutic strategy to directly block pathologic cell death.
