First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.
Cell
; 187(7): 1666-1684.e26, 2024 Mar 28.
Article
in En
| MEDLINE
| ID: mdl-38490194
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Liver Failure
/
MAP Kinase Kinase 4
/
Enzyme Inhibitors
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell
Year:
2024
Document type:
Article
Affiliation country:
Germany
Country of publication:
United States