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

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.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS9434 | MetaboLights | 2024-09-23

REPOSITORIES: MetaboLights

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

Zwirner Stefan S Abu Rmilah Anan A AA Klotz Sabrina S Pfaffenroth Bent B Kloevekorn Philip P Moschopoulou Athina A AA Schuette Svenja S Haag Mathias M Selig Roland R Li Kewei K Zhou Wei W Nelson Erek E Poso Antti A Chen Harvey H Amiot Bruce B Jia Yao Y Minshew Anna A Michalak Gregory G Cui Wei W Rist Elke E Longerich Thomas T Jung Birgit B Felgendreff Philipp P Trompak Omelyan O Premsrirut Prem K PK Gries Katharina K Muerdter Thomas E TE Heinkele Georg G Wuestefeld Torsten T Shapiro David D Weissbach Markus M Koenigsrainer Alfred A Sipos Bence B Ab Eiso E Zacarias Magdalena Ortiz MO Theisgen Stephan S Gruenheit Nicole N Biskup Saskia S Schwab Matthias M Albrecht Wolfgang W Laufer Stefan S Nyberg Scott S Zender Lars L

Cell 20240314 7

PMID: 38490194

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