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Pharmacologic arm-selective unfolded protein response (UPR) signaling pathway activation is emerging as a promising strategy to ameliorate imbalances in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. The small molecule  N- (2-hydroxy-5-methylphenyl)-3-phenylpropanamide ( 147 ) was previously identified ( Plate et al., 2016 ) to preferentially activate the ATF6 arm of the UPR, promoting protective remodeling of the ER proteostasis network. Here we show that  147 -dependent ATF6 activation requires metabolic oxidation to form an electrophile that preferentially reacts with ER proteins. Proteins covalently modified by  147  include protein disulfide isomerases (PDIs), known to regulate ATF6 activation. Genetic depletion of PDIs perturbs  147 -dependent induction of the ATF6-target gene,  BiP , implicating covalent modifications of PDIs in the preferential activation of ATF6 afforded by treatment with  147 . Thus,  147  is a pro-drug that preferentially activates ATF6 signaling through a mechanism involving localized metabolic activation and selective covalent modification of ER resident proteins that regulate ATF6 activity.

Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins