Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator
A series of activators targeting GCN2 (general control nonderepressible 2) kinase has been developed, culminating in HC-7366, which is now in clinical trials as an antitumor therapy. Through optimization, these compounds achieved enhanced permeability compared to the original indazole hinge-binding scaffold while retaining high potency for GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase).
Improved ADME properties enabled robust in vivo exposure in rats and mice, supporting HC-7366’s use in xenograft models. In these studies, HC-7366 effectively activated the GCN2 pathway, resulting in significant tumor growth inhibition.