Rhomboid intramembrane proteases, first discovered in 2001, have intrigued scientists with their unique biochemistry, but the biological functions of many members of this enzyme class remain poorly defined. The mitochondrial rhomboid protease PARL has been proposed to play a critical role in regulating apoptosis and mitophagy, and the identification of its specific physiological substrates as well as its involvement in the pathophysiology of type 2 diabetes and Parkinson’s disease represent active areas of study. By employing competitive activity-based protein profiling technology with fluorophosphonate (FP) probes, we have conducted a screen for inhibitors of mouse and human PARL. Through these studies, we have identified new chemical scaffolds, including sulfonates of <i>N</i>-hydroxyimides, that are capable of inhibiting PARL as well as other members of the rhomboid protease class. These compounds can serve as the basis for new chemical tools to both probe the biology of rhomboid proteases and examine the ability of members of this family to serve as medicinal targets.

Development of small molecule inhibitors for rhomboid intramembrane proteases

2019 Fall National Meeting

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