| First Author | Zwirner S | Year | 2024 |
| Journal | Cell | Volume | 187 |
| Issue | 7 | Pages | 1666-1684.e26 |
| PubMed ID | 38490194 | Mgi Jnum | J:346584 |
| Mgi Id | MGI:7618039 | Doi | 10.1016/j.cell.2024.02.023 |
| Citation | Zwirner S, et al. (2024) First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure. Cell 187(7):1666-1684.e26 |
| abstractText | 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. |
