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

28. März, 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

Abstract

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.

  1. Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany; HepaRegeniX GmbH, Tübingen 72072, Germany.
  2. William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA.
  3. Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany.
  4. Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen 72076, Germany.
  5. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart 70376, Germany.
  6. HepaRegeniX GmbH, Tübingen 72072, Germany; Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen 72076, Germany.
  7. Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany; School of Pharmacy, University of Eastern Finland, Kuopio 70211, Finland; iFIT Cluster of Excellence (EXC 2180) “Image-guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72076, Germany.
  8. Institute of Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany.
  9. HepaRegeniX GmbH, Tübingen 72072, Germany.
  10. Mirimus Inc, 760 Parkside Ave, Brooklyn, NY 11226, USA.
  11. Laboratory for In Vivo Genetics & Gene Therapy, Genome Institute of Singapore, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138672, Singapore; School of Biological Sciences, Nanyang Technological University of Singapore, Singapore 637551, Singapore.
  12. iFIT Cluster of Excellence (EXC 2180) “Image-guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72076, Germany; German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of General-, Visceral, and Transplant Surgery, University Hospital Tübingen, Tübingen 72076, Germany.
  13. ZoBio B.V., Leiden 2333 CH, the Netherlands.
  14. CeGaT GmbH, Tübingen 72076, Germany.
  15. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart 70376, Germany; iFIT Cluster of Excellence (EXC 2180) “Image-guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72076, Germany; Department of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tübingen, Tübingen 72076, Germany.
  16. Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen 72076, Germany; Tübingen Center for Academic Drug Discovery & Development (TüCAD(2)), Tübingen 72076, Germany. Electronic address: stefan.laufer@uni-tuebingen.de.
  17. William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: nyberg.scott@mayo.edu.
  18. Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany; iFIT Cluster of Excellence (EXC 2180) “Image-guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72076, Germany; German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Tübingen Center for Academic Drug Discovery & Development (TüCAD(2)), Tübingen 72076, Germany. Electronic address: lars.zender@med.uni-tuebingen.de.