Physiological and pharmacological modulation of BAX

Bcl-2-associated X protein (BAX) is a critical executioner of mitochondrial regulated cell death through its lethal activity of permeabilizing the mitochondrial outer membrane (MOM). While the physiological function of BAX ensures tissue homeostasis, dysregulation of BAX leads to aberrant cell death. Despite BAX being a promising therapeutic target for human diseases, historically the development of drugs has focused on antiapoptotic BCL-2 proteins, due to challenges in elucidating the mechanism of BAX activation and identifying druggable surfaces of BAX. Here, we discuss recent studies that have provided structure–function insights and identified regulatory surfaces that control BAX activation. Moreover, we emphasize the development of small molecule orthosteric, allosteric, and oligomerization modulators that provide novel opportunities for biological investigation and progress towards drugging BAX. A growing number of peptides, antibodies, and structurally diverse small molecules have been reported as direct modulators of BAX.BAX can be activated or inhibited via multiple distinct binding sites and mechanisms.Mechanistic studies of physiological and synthetic BAX modulators have provided important insights into the BAX activation pathway and apoptosis.BAX activators and inhibitors have shown promising activity in in vivo models of cancer, cardiomyopathy, and neurodegenerative disease.A thorough understanding of BAX binding sites and the key features of active pharmacophores will allow further development of clinically useful BAX modulators.