Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development

Abstract

We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

Keywords: PERK; UPR; fluorine interaction; kinase; lead optimization; structure−activity relationship.

Figure 1

Crystal structure of compound 6 bound to the PERK kinase domain. (a) Close-up view of 6 (green sticks) in the PERK active site (brown cartoon and sticks). The 6-methylpyridyl group occupies the large inner lipophilic pocket, while the fluoroindoline fills a narrow channel between M887 and D954 of the inward facing DFG motif. The amino-pyrimidine binds the hinge β-strand with hydrogen bonds to the backbone amide atoms of Q888 and C890. (b) Close-up view of 6 bound to the PERK active site with surface rendering. Close spatial arrangement between the indoline fluorine atom and the V606 methyl groups may account for some of the improved biochemical activity. Atomic interactions are indicated with orange solid lines and distances reported in Angstroms. The crystal structure of compound 6 bound to the PERK kinase domain is available with the PDB access code 4M7I .