Discovery of 7-Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1<i>H</i>-indol-5-yl)-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK)
Jeffrey M. Axten(GlaxoSmithKline (United States)), Jesús R. Medina(GlaxoSmithKline (United States)), Yanhong Feng(GlaxoSmithKline (United States)), Arthur Y. L. Shu(GlaxoSmithKline (United States)), Stuart P. Romeril(GlaxoSmithKline (United States)), Seth W. Grant(GlaxoSmithKline (United States)), William Hoi Hong Li(GlaxoSmithKline (United States)), Dirk A. Heerding(GlaxoSmithKline (United States)), Elisabeth A. Minthorn(GlaxoSmithKline (United States)), Thomas Mencken(GlaxoSmithKline (United States)), Charity Atkins(GlaxoSmithKline (United States)), Qi Liu(GlaxoSmithKline (United States)), Sridhar K. Rabindran(GlaxoSmithKline (United States)), Rakesh Kumar(GlaxoSmithKline (United States)), Xuan Hong, Aaron S. Goetz, Thomas B. Stanley, J. David Taylor, Scott Sigethy, Ginger H. Tomberlin, Annie M. Hassell, Kirsten M. Kahler, Lisa M. Shewchuk, Robert T. Gampe
Cited by 615Open Access
Abstract
Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.
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