2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2012 Aug 23;55(16):7193-207. doi: 10.1021/jm300713s.
Jeffrey M Axten 1,  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
Affiliations

Affiliation

  • 1 Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development, Collegeville, Pennsylvania 19426, United States. Jeffrey.M.Axten@gsk.com
PMID: 22827572 DOI: 10.1021/jm300713s
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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