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.
Subject(s)
Protein Serine-Threonine Kinases , eIF-2 Kinase , Humans , Mice , Rats , Animals , Protein Serine-Threonine Kinases/metabolism , eIF-2 Kinase/metabolism , Mice, Inbred C57BL , RNA , Endoplasmic Reticulum/metabolismABSTRACT
Photogenic: The synthesis of linderaspironeâ A has been accomplished in only three steps by a Darzens cyclopentenedione synthesis and dioxygen-assisted photochemical dimerization. Moreover, the thermal isomerization of linderaspironeâ A into bi-linderone has been discovered, which may give clues to the biosynthetic pathway for bi-linderone.
