FICD inhibitor C22 is a specific, cell-permeable inhihitor of the AMP transferase FICD, significantly inhibits endogenous FICD-mediated BiP AMPylation (IC50=7.27 uM) while weakly inhibiting BiP deAMPylation. C22 may bind to the dimer interface of endogenous FICD and prevent the dimeric deAMPylase-competent FICD from adopting an AMPylase-competent conformation. C22 is noncytotoxic that do not trigger the UPRER and are effective against pathogenic FICD mutants in vitro. C22 improves proinsulin folding and secretion in pancreatic β cells by reducing basal BiP AMPylation. Human FICD, also referred to as Huntingtin yeast-interacting partner E (HYPE), localizes to the ER lumen and is N-glycosylated on Asn275.
