Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator
Christopher G. Thomson, Thomas D. Aicher, Weiwei Cheng, Hongwen Du, Crissy Dudgeon, An‐Hu Li, Baozhong Li, Eric S. Lightcap, Diheng Luo, Mark J. Mulvihill, Pengwei Pan, Benjamin F. Rahemtulla, Alan C. Rigby, Bradley Sherborne, Sanjeev Sood, David Surguladze, Eric P. A. Talbot, Feven Tameire, S. Taylor, Yi Wang, Paulina M. Wojnarowicz, Fenfen Xiao, Savithri Ramurthy
Abstract
A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.