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 In
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- 作者：Jeffrey M. Axten ; Jes煤s 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：August 23, 2012
- 年：2012
- 卷：55
- 期：16
- 页码：7193-7207
- 全文大小：586K
- 年卷期：v.55,no.16(August 23, 2012)
- ISSN：1520-4804
文摘
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.