Gene correlation analysis between an shRNA vs. small molecule inhibitor targeting MKK4

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end stage liver disease. We here report on the structure-based development and characterization (NMR-spectroscopy) of first-in-class small molecule inhibitors of the dual specific kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model and showed antisteatotic and antifibrotic effects in liver disease mouse models. A phase I trial with the clinical candidate HRX215 revealed excellent safety and pharmacokinetics in humans. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.