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

March 28, 2024

Stefan Zwirner 1, Anan A Abu Rmilah 2, Sabrina Klotz 3, Bent Pfaffenroth 4, Philip Kloevekorn 4, Athina A Moschopoulou 3, Svenja Schuette 3, Mathias Haag 5, Roland Selig 6, Kewei Li 2, Wei Zhou 2, Erek Nelson 2, Antti Poso 7, Harvey Chen 2, Bruce Amiot 2, Yao Jia 2, Anna Minshew 2, Gregory Michalak 2, Wei Cui 3, Elke Rist 3, Thomas Longerich 8, Birgit Jung 9, Philipp Felgendreff 2, Omelyan Trompak 3, Prem K Premsrirut 10, Katharina Gries 3, Thomas E Muerdter 5, Georg Heinkele 5, Torsten Wuestefeld 11, David Shapiro 9, Markus Weissbach 9, Alfred Koenigsrainer 12, Bence Sipos 3, Eiso Ab 13, Magdalena Ortiz Zacarias 13, Stephan Theisgen 13, Nicole Gruenheit 14, Saskia Biskup 14, Matthias Schwab 15, Wolfgang Albrecht 9, Stefan Laufer 16, Scott Nyberg 17, Lars Zender 18


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.

Keywords: MKK4; drug discovery and development; first-in-human phase I trial; liver; liver failure; liver regeneration; partial hepatectomy.