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)

• Published in: Journal of medicinal chemistry Vol. 55; no. 16; pp. 7193 - 7207
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.08.2012; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: Adenine - analogs & derivatives; Adenine - chemical synthesis; Adenine - chemistry; Adenine - pharmacology; Administration, Oral; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological Availability; Cell Line, Tumor; Chemistry, Medicinal; Crystallography, X-Ray; Dogs; Drug Screening Assays, Antitumor; eIF-2 Kinase - antagonists & inhibitors; Female; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Life Sciences & Biomedicine; Male; Mice; Mice, Nude; Models, Molecular; Neoplasm Transplantation; Pharmacology & Pharmacy; Phosphorylation; Protein Conformation; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Transplantation, Heterologous; ACTIVATION; DESIGN; TRANSLATION; HYPOXIA; STRESS-RESPONSE; PEK
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300713s

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.