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

• Main Authors: Zwirner, Stefan, Rmilah, Anan A. Abu, Klotz, Sabrina, Pfaffenroth, Bent, Kloevekorn, Philip, Moschopoulou, Athina A., Schuette, Svenja, Haag, Mathias, Selig, Roland, Li, Kewei, Zhou, Wei, Nelson, Erek, Poso, Antti, Chen, Harvey, Amiot, Bruce, Jia, Yao, Minshew, Anna, Michalak, Gregory, Cui, Wei, Rist, Elke, Longerich, Thomas, Jung, Birgit, Felgendreff, Philipp, Trompak, Omelyan, Premsrirut, Prem K., Gries, Katharina, Muerdter, Thomas E., Heinkele, Georg, Wuestefeld, Torsten, Shapiro, David, Weissbach, Markus, Koenigsrainer, Alfred, Sipos, Bence, Ab, Eiso, Zacarias, Magdalena Ortiz, Theisgen, Stephan, Gruenheit, Nicole, Biskup, Saskia, Schwab, Matthias, Albrecht, Wolfgang, Laufer, Stefan, Nyberg, Scott, Zender, Lars
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2024
• Subjects: Medicine, Health and Life Sciences; Drug discovery and development; Liver failure
• Online Access: https://hdl.handle.net/10356/178695
• Institution: Nanyang Technological University

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.