title: 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).
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.
authors: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development, Collegeville, Pennsylvania 19426, United States. Jeffrey.M.Axten@gsk.com
authors: Jeffrey M
authors: JM
authors: Axten
authors: Jesús R
authors: JR
authors: Medina
authors: Yanhong
authors: Y
authors: Feng
authors: Arthur
authors: A
authors: Shu
authors: Stuart P
authors: SP
authors: Romeril
authors: Seth W
authors: SW
authors: Grant
authors: William Hoi Hong
authors: WH
authors: Li
authors: Dirk A
authors: DA
authors: Heerding
authors: Elisabeth
authors: E
authors: Minthorn
authors: Thomas
authors: T
authors: Mencken
authors: Charity
authors: C
authors: Atkins
authors: Qi
authors: Q
authors: Liu
authors: Sridhar
authors: S
authors: Rabindran
authors: Rakesh
authors: R
authors: Kumar
authors: Xuan
authors: X
authors: Hong
authors: Aaron
authors: A
authors: Goetz
authors: Thomas
authors: T
authors: Stanley
authors: J David
authors: JD
authors: Taylor
authors: Scott D
authors: SD
authors: Sigethy
authors: Ginger H
authors: GH
authors: Tomberlin
authors: Annie M
authors: AM
authors: Hassell
authors: Kirsten M
authors: KM
authors: Kahler
authors: Lisa M
authors: LM
authors: Shewchuk
authors: Robert T
authors: RT
authors: Gampe
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors*
chemical_list: D000225:Adenine; D000970:Antineoplastic Agents; D007211:Indoles; D011743:Pyrimidines; D011758:Pyrroles; D019892:eIF-2 Kinase; C576403:7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine