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

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

Cell

10.1016/j.cell.2024.02.023

https://doi.org/10.1016/j.cell.2024.02.023

Stefan Zwirner, Anan A. Abu Rmilah, Sabrina Klotz, Bent Pfaffenroth, Philip Kloevekorn, Athina A. Moschopoulou, 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 Zacarias, Stephan Theisgen, Nicole Gruenheit, Saskia Biskup, Matthias Schwab, Wolfgang Albrecht, Stefan Laufer, Scott Nyberg, Lars Zender

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

14 March 2024

Zwirner, S., Abu Rmilah, A. A., Klotz, S., Pfaffenroth, B., Kloevekorn, P., Moschopoulou, A. A., Schuette, S., Haag, M., Selig, R., Li, K., Zhou, W., Nelson, E., Poso, A., Chen, H., Amiot, B., Jia, Y., Minshew, A., Michalak, G., Cui, W., … Zender, L. (2024). First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure. Cell, 187(7), 1666-1684.e26. https://doi.org/10.1016/j.cell.2024.02.023

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.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

There was no specific funding for the research done

https://oar.a-star.edu.sg/communities-collections/articles/22590

0092-8674

Genome Institute of Singapore

https://doi.org/10.1016/j.cell.2024.02.023