AA147 is a small molecule activator of the AFT6 branch of the Unfolded Protein Response (UPR), a stress-responsive signaling pathway that mitigates the misfolding of proteins and upregulates the scavenging of damaging Reactive Oxygen Species (ROS). However, constant activation of the UPR by AA147 can lead to liver disease, and in extreme cases, apoptosis. To avoid chronic and off-target ATF6 activation, the Cooley Lab is working to develop various prodrugs of AA147 that are biologically inactive until encountering diseased tissue, such as heart tissue following an ischemia-reperfusion event, or heart attack. As ROS levels are highly upregulated following an ischemia-reperfusion event, a prodrug was designed and synthesized that would release AA147 into diseased tissue through a reaction with hydrogen peroxide, a type of ROS. Although the prodrug was able to release AA147 and provide significant protection to primary cardiomyocytes following an ischemia-reperfusion challenge, the initially designed prodrug exhibited relatively slow release kinetics due to the rate-limiting 1,6-elimination linker. To increase the AA147 release kinetics and downstream protection of heart tissue, we have designed a series of new prodrugs designed to increase the kinetics of therapeutic release and improve biological activity. Progress on the synthesis, physiological stability, and release kinetics upon peroxide administration of these new AA147 ROS-activatable prodrugs will be discussed.

Synthesis and evaluation of disease-targeted ROS-activated prodrugs

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