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

ACS Med Chem Lett. 2013 Aug 12;4(10):964-8. doi: 10.1021/ml400228e. eCollection 2013 Oct 10.


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.