Q1 · BIOLOGY
Article
Author: Zacarias, Magdalena Ortiz ; Koenigsrainer, Alfred ; Chen, Harvey ; Haag, Mathias ; Zwirner, Stefan ; Sipos, Bence ; Laufer, Stefan ; Amiot, Bruce ; Jia, Yao ; Zhou, Wei ; Abu Rmilah, Anan A ; Moschopoulou, Athina A ; Heinkele, Georg ; Rist, Elke ; Longerich, Thomas ; Trompak, Omelyan ; Gruenheit, Nicole ; Klotz, Sabrina ; Felgendreff, Philipp ; Albrecht, Wolfgang ; Shapiro, David ; Nyberg, Scott ; Nelson, Erek ; Biskup, Saskia ; Theisgen, Stephan ; Michalak, Gregory ; Muerdter, Thomas E ; Gries, Katharina ; Schuette, Svenja ; Premsrirut, Prem K ; Kloevekorn, Philip ; Selig, Roland ; Weissbach, Markus ; Pfaffenroth, Bent ; Poso, Antti ; Zender, Lars ; Ab, Eiso ; Cui, Wei ; Minshew, Anna ; Li, Kewei ; Jung, Birgit ; Wuestefeld, Torsten ; Schwab, Matthias
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.