Ubiquitin pathway modulators for treating pancreatitis

New approaches are needed to treat acute and chronic pancreatitis which is a major health problem in the US. One novel approach is to promote mitochondrial health to protect pancreas from damages caused by various stressors. We have identified important roles for mitophagy in resistance to pancreatitis. These new findings, in the setting of the urgent medical need for new approaches to treat pancreatitis, led to this new SBIR application to fully leverage prior discoveries. Ubiquitin proteasome system (UPS) is a key regulator of autophagic clearance of damaged mitochondria. As such, activation of ubiquitin pathway enzyme critically involved in promoting mitochondrial health is expected to have therapeutic effects. Pogenra’s UbiProTM drug discovery platform was employed to discover novel, potent and selective activators of UPS enzymes. We demonstrated that UPS activator inhibited pancreatitis in vivo. In this Phase I grant, we propose to evaluate these novel molecules for their efficacy in cellular and animal models of acute and chronic pancreatitis and perform mechanism of action studies. The ultimate commercial goal of this project is the development of small molecule UPS activators as novel drugs that could treat pancreatitis.