MKK4 Inhibition Provokes Greater Liver Regeneration

Researchers here report on an approach to meaningfully stimulate the regenerative capacity of the liver. The liver is one of the few organs capable of significant regrowth in mammals, and the way in which it does so is quite different from the regenerative response found in other tissues. Thus while the results here are quite impressive, they don't apply to other organs. This is purely a way to manipulate the regulation of liver regeneration.

One key feature of acute and chronic liver diseases, and after extended liver resections, is the inability of hepatocytes to sufficiently regenerate and restore or maintain a critical functional liver mass. Although healthy livers harbor a nearly unlimited regenerative potential, damage-associated changes in the hepatic microenvironment of acutely or chronically injured livers diminish the hepatocytes' regenerative capacity. Unfortunately, the underlying molecular mechanisms are poorly understood.

We recently reported on the discovery of the dual specific kinase MKK4 as a master regulator of hepatocyte regeneration. MKK4 is a MAP2 kinase and part of the stress-activated protein kinase (SAPK)/mitogen-activated protein kinase (MAPK) signaling networks. MKK4 can be activated upon a cell's exposure to different stress stimuli. Short hairpin RNA (shRNA) mediated silencing of MKK4 was found to unlock endogenous regenerative capacity of hepatocytes in acutely or chronically injured livers via derouting SAPK signaling predominantly through MKK7 and JNK1 toward a downstream pro-regenerative transcriptional program mediated by ATF2 and ELK1. Unfortunately, no small molecule inhibitors for selective MKK4 inhibition are available.

We here report on the development and in vitro and in vivo characterization of first-in-class small molecule inhibitors of the dual specific kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models. Strikingly, treatment with the clinical candidate HRX215 prevented post-hepatectomy-liver-failure (PHLF) and allowed for the survival of pigs in a lethal 85% hepatectomy model, suggesting that boosted liver regeneration by HRX215 might represent a viable treatment option for human PHLF and the pathogenetically related small for-size syndrome (SFSS) after liver transplantation. Testing of HRX215 in a phase I trial in 48 healthy volunteers revealed excellent safety, tolerability, and pharmacokinetics (PKs) of HRX215. Clinical trials to probe HRX215 as a therapeutic option to prevent/treat liver failure after extensive oncological liver resections or after transplantation of small liver grafts are warranted.