%0 Journal Article %A Palmer, Jonathan E. %A Brietske, Breanna M. %A Bate, Tyler C. %A Blackwood, Erik A. %A Garg, Manasa %A Glembotski, Christopher C. %A Cooley, Christina B. %D 2019 %T Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury %U https://acs.figshare.com/articles/journal_contribution/Reactive_Oxygen_Species_ROS_-Activatable_Prodrug_for_Selective_Activation_of_ATF6_after_Ischemia_Reperfusion_Injury/10269692 %R 10.1021/acsmedchemlett.9b00299.s001 %2 https://acs.figshare.com/ndownloader/files/18548105 %K ER-resident cytochrome P 450 enzymes %K protein misfolding maladies %K peroxide-mediated activation %K ROS-activatable prodrug 1 %K pathway activation %K ATF 6 %K Selective Activation %K Reactive Oxygen Species %K Cyp 1A %K Biological evaluation %K molecule ATF 6 activator %K injury %K peroxide-mediated toxicity %K reactive oxygen species %K target ATF 6 activation %K Prodrug 1 blocks activity %X We describe here the design, synthesis, and biological evaluation of a reactive oxygen species (ROS)-activatable prodrug for the selective delivery of 147, a small molecule ATF6 activator, for ischemia/reperfusion injury. ROS-activatable prodrug 1 and a negative control unable to release free drug were synthesized and examined for peroxide-mediated activation. Prodrug 1 blocks activity of 147 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 1 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. %I ACS Publications