Discovery of 7‑Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro‑1H‑indol-5-yl)‑7H‑pyrrolo[2,3‑d]pyrimidin-4-amine (GSK2606414), a Potent and Selective
First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic
Reticulum Kinase (PERK)

Axten, Jeffrey M.; Medina, Jesús R.; Feng, Yanhong; Shu, Arthur; Romeril, Stuart
P.; Grant, Seth W.; Hoi Hong Li, William; 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.

doi:10.1021/jm300713s.s001

jm300713s_si_001.pdf (276.3 kB)

Discovery of 7‑Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro‑1H‑indol-5-yl)‑7H‑pyrrolo[2,3‑d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK)

journal contribution

posted on 2012-08-23, 00:00 authored by Jeffrey M. Axten, Jesús R. Medina, Yanhong Feng, Arthur Shu, Stuart P. Romeril, Seth W. Grant, William Hoi Hong Li, Dirk A. Heerding, Elisabeth Minthorn, Thomas Mencken, Charity Atkins, Qi Liu, Sridhar Rabindran, Rakesh Kumar, Xuan Hong, Aaron Goetz, Thomas Stanley, J. David Taylor, Scott D. Sigethy, Ginger H. Tomberlin, Annie M. Hassell, Kirsten M. Kahler, Lisa M. Shewchuk, Robert T. Gampe

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.