Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury PalmerJonathan E. BrietskeBreanna M. BateTyler C. BlackwoodErik A. GargManasa GlembotskiChristopher C. CooleyChristina B. 2019 We describe here the design, synthesis, and biological evaluation of a reactive oxygen species (ROS)-activatable prodrug for the selective delivery of <b>147</b>, a small molecule ATF6 activator, for ischemia/reperfusion injury. ROS-activatable prodrug <b>1</b> and a negative control unable to release free drug were synthesized and examined for peroxide-mediated activation. Prodrug <b>1</b> blocks activity of <b>147</b> by its inability to undergo metabolic oxidation by ER-resident cytochrome P450 enzymes such as Cyp1A2, probed directly here for the first time. Biological evaluation of ROS-activatable prodrug <b>1</b> in primary cardiomyocytes demonstrates protection against peroxide-mediated toxicity and enhances viability following simulated I/R injury. The ability to selectively target ATF6 activation under diseased conditions establishes the potential for localized stress-responsive signaling pathway activation as a therapeutic approach for I/R injury and related protein misfolding maladies.