Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury
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.
American Chemical Society
Palmer, J. E., Brietske, B. M., Bate, T. C., Blackwood, E. A., Garg, M., Glembotski, C. C., & Cooley, C. B. (2020). Reactive oxygen species (ROS)-activatable prodrug for selective activation of ATF6 after ischemia/reperfusion injury. ACS Medicinal Chemistry Letters, 11(3), 292-297. http://doi.org/10.1021/acsmedchemlett.9b00299
ACS Medicinal Chemistry Letters