Inhibitors of DHHC family proteins

Abstract

Protein S-acylation is a prevalent post-translational protein lipidation that is dynamically regulated by ‘writer’ protein S-acyltransferases and ‘eraser’ acylprotein thioesterases. The protein S-acyltransferases comprise 23 aspartate–histidine–histidine–cysteine (DHHC)–containing proteins, which transfer fatty acid acyl groups from acyl-coenzyme A onto protein substrates. DHHC proteins are increasingly recognized as critical regulators of S-acylation–mediated cellular processes and pathology. As our understanding of the importance and breadth of DHHC-mediated biology and pathology expands, so too does the need for chemical inhibitors of this class of proteins. In this review, we discuss the challenges and progress in DHHC inhibitor development, focusing on 2-bromopalmitate, the most commonly used inhibitor in the field, and N-cyanomethyl-N-myracrylamide, a new broad-spectrum DHHC inhibitor. We believe that current and ongoing advances in structure elucidation, mechanistic interrogation, and novel inhibitor design around DHHC proteins will spark innovative strategies to modulate these critical proteins in living systems.