biostudies-literatureUnknown4(10)Axten JMWe 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.ACS medicinal chemistry letters964-8https://www.ebi.ac.uk/biostudies/studies/S-EPMC4027568biostudies-literatureDiscovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development.PMC4027568Shu AHassell AMFeng YMencken TAtkins CGaul NLi WHGrant SWMinthorn EStanley TGoetz AKumar RAxten JMGampe RTRomeril SPRalph JMedina JRHeerding DAfalseDiscovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development.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.2013-01-01T00:00:00Z2013 Oct2025-04-22T17:34:49.902Z2019-03-27T01:28:34ZS-EPMC40275682490059310.1021/ml400228e