First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure

• DOI: 10.1016/j.cell.2024.02.023
• Publication Date: 2024-03-14T14:37:57Z
• Authors: Stefan Zwirner; Anan A. Abu Rmilah; Sabrina Klotz; Bent Pfaffenroth; Philip Kloevekorn; Athina A. Moschop...; Svenja Schuette; Mathias Haag; Roland Selig; Kewei Li; Wei Zhou; Erek Nelson; Antti Poso; Harvey Chen; Bruce Amiot; Yao Jia; Anna Minshew; Gregory Michalak; Wei Cui; Elke Rist; Thomas Longerich; Birgit Jung; Philipp Felgendreff; Omelyan Trompak; Prem K. Premsrirut; Katharina Gries; Thomas E. Muerdter; Georg Heinkele; Torsten Wuestefeld; David Shapiro; Markus Weissbach; Alfred Koenigsrainer; Bence Sipos; Eiso AB; Magdalena Ortiz Z...; Stephan Theisgen; Nicole Gruenheit; Saskia Biskup; Matthias Schwab; Wolfgang Albrecht; Stefan Laufer; Scott Nyberg; Lars Zender
• Keywords: 570; Swine; MAP Kinase Kinase 4; Liver Diseases; 610; Article; Liver Regeneration; Mice; Liver; Hepatocytes; Animals; Humans; Hepatectomy; Enzyme Inhibitors; Liver Failure

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. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity 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 first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.