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

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

doi:10.1016/j.cell.2024.02.023

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

Journal article

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

Stefan Zwirner, Anan A. Abu Rmilah, Sabrina Klotz, Bent Pfaffenroth, Philip Kloevekorn, Athina A. Moschopoulou, Svenja Schuette, Mathias Haag, Roland Selig, Kewei Li, …

Cell, Vol.187(7), pp.1666-1684.e26

03/28/2024

DOI: 10.1016/j.cell.2024.02.023

PMCID: PMC11011246

PMID: 38490194

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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. [Display omitted] •A first-in-class small-molecule-based MKK4 inhibitor was developed (HRX215)•HRX215 increased liver regeneration after hepatectomy in murine and porcine models•HRX215 treatment allowed for survival of pigs in a lethal 85% hepatectomy model•A phase I trial revealed safety and excellent pharmacokinetics of HRX215 in humans A targeted therapy against the kinase MKK4 was developed (HRX215) and investigated preclinically, as well as in a phase I study in humans. HRX215 boosted liver regeneration, prevented liver failure after extensive hepatectomy in pigs, and holds the promise to prevent liver failure after extensive oncological liver resections or transplantation of small liver grafts in humans.

drug discovery and development

first-in-human phase I trial

liver

liver failure

liver regeneration

MKK4

partial hepatectomy

Details

Title: Subtitle: First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure
Creators: Stefan Zwirner - University Children's Hospital Tübingen
Anan A. Abu Rmilah - Mayo Clinic
Sabrina Klotz - University Children's Hospital Tübingen
Bent Pfaffenroth - University of Tübingen
Philip Kloevekorn - University of Tübingen
Athina A. Moschopoulou - University Children's Hospital Tübingen
Svenja Schuette - University Children's Hospital Tübingen
Mathias Haag - Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Roland Selig - University of Tübingen
Kewei Li - Mayo Clinic
Wei Zhou - Mayo Clinic
Erek Nelson - Mayo Clinic
Antti Poso - University of Tübingen
Harvey Chen - Mayo Clinic
Bruce Amiot - Mayo Clinic
Yao Jia - Mayo Clinic
Anna Minshew - Mayo Clinic
Gregory Michalak - Mayo Clinic
Wei Cui - University Children's Hospital Tübingen
Elke Rist - University Children's Hospital Tübingen
Thomas Longerich - Heidelberg University
Birgit Jung - HepaRegeniX GmbH, Tübingen 72072, Germany
Philipp Felgendreff - Mayo Clinic
Omelyan Trompak - University Children's Hospital Tübingen
Prem K. Premsrirut - Mirimus Inc, 760 Parkside Ave, Brooklyn, NY 11226, USA
Katharina Gries - University Children's Hospital Tübingen
Thomas E. Muerdter - Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Georg Heinkele - Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Torsten Wuestefeld - Agency for Science, Technology and Research
David Shapiro - HepaRegeniX GmbH, Tübingen 72072, Germany
Markus Weissbach - HepaRegeniX GmbH, Tübingen 72072, Germany
Alfred Koenigsrainer - University Children's Hospital Tübingen
Bence Sipos - University Children's Hospital Tübingen
Eiso AB - ZoBio B.V., Leiden 2333 CH, the Netherlands
Magdalena Ortiz Zacarias - ZoBio B.V., Leiden 2333 CH, the Netherlands
Stephan Theisgen - ZoBio B.V., Leiden 2333 CH, the Netherlands
Nicole Gruenheit - CeGaT (Germany)
Saskia Biskup - CeGaT (Germany)
Matthias Schwab - Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Wolfgang Albrecht - HepaRegeniX GmbH, Tübingen 72072, Germany
Stefan Laufer - University of Tübingen
Scott Nyberg - Mayo Clinic
Lars Zender - German Cancer Research Center
Resource Type: Journal article
Publication Details: Cell, Vol.187(7), pp.1666-1684.e26
DOI: 10.1016/j.cell.2024.02.023
PMID: 38490194
PMCID: PMC11011246
NLM abbreviation: Cell
ISSN: 0092-8674
eISSN: 1097-4172
Publisher: Elsevier Inc
Language: English
Date published: 03/28/2024
Academic Unit: Internal Medicine
Record Identifier: 9984845393802771

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