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Axten, Jeffrey M; Medina, Jesús R; Feng, Yanhong; Shu, Arthur; Romeril, Stuart P; Grant, Seth W; Li, William Hoi Hong; Heerding, Dirk A; Minthorn, Elisabeth; Mencken, Thomas; Atkins, Charity; Liu, Qi; Rabindran, Sridhar; Kumar, Rakesh; Hong, Xuan; Goetz, Aaron; Stanley, Thomas; Taylor, J. David; Sigethy, Scott D; Tomberlin, Ginger H; Hassell, Annie M; Kahler, Kirsten M; Shewchuk, Lisa M; Gampe, Robert T
Journal of medicinal chemistry, 08/2012, Volume: 55, Issue: 16Journal Article
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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