Darizmetinib (HRX215): A Promising 1st-in-Class Liver Regenerating Drug in Phase 1b/2a Clinical Development, Targeting the Stress Signaling Protein Kinase MKK4

High Resolution Image Download MS PowerPoint Slide Mitogen-activated protein kinase kinase 4 (MKK4), a MAP2 kinase that activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase, is a key kinase of the stress-activated protein kinase (SAPK)/mitogen-activated protein kinase (MAPK) signaling network. Inhibition of MKK4 represents a novel therapeutic approach by leveraging a rerouting mechanism within the signaling network, predominantly via MKK7 and JNK1, to modulate the regenerative capacity of hepatocytes. In this study, we describe the discovery of darizmetinib (HRX215), a first-in-class MKK4 inhibitor currently in clinical development. Darizmetinib was derived from a known BRaf inhibitor, and through extensive structure–activity relationship (SAR) studies, we successfully engineered potency and selectivity for MKK4 while eliminating the original BRaf on-target activity. Preclinical proof-of-concept studies, along with in vivo evaluations of different lead candidates, identified darizmetinib, demonstrating dose-dependent efficacy across various disease-relevant pharmacological models.