Novel MST1 inhibitor accelerates murine liver regeneration following partial hepatectomy with improved survival in models of steatohepatitis

Disrupted hepatocyte regeneration following surgical resection remains a clinical problem with few therapeutic options. The current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration may provide an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration in both normal and diseased murine preclinical models. mCLC846 demonstrated on target inhibition of MST1 and reduced EGFR inhibition which resulted in Yes-associated protein (YAP) activation. Oral delivery of mCLC846 perioperatively resulted in accelerated liver regeneration and improved survival in diet induced NASH models. Transcriptional analysis suggested that mCLC846 enhanced the normal regenerative pathways induced following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided survival benefit in models of diet induced non-alcoholic steatohepatitis. Overall design: Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a novel small molecule inhibitor targeting MST1 with reduced off target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy which included models of diet induced NASH.