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)

被引：503

作者：

Axten, Jeffrey M. ^{[1
]}

Medina, Jesus R. ^{[1
]}

Feng, Yanhong ^{[1
]}

Shu, Arthur ^{[1
]}

Romeril, Stuart P. ^{[1
]}

Grant, Seth W. ^{[1
]}

Li, William Hoi Hong ^{[1
]}

Heerding, Dirk A. ^{[1
]}

Minthorn, Elisabeth ^{[1
]}

Mencken, Thomas ^{[1
]}

Atkins, Charity ^{[1
]}

Liu, Qi ^{[1
]}

Rabindran, Sridhar ^{[1
]}

Kumar, Rakesh ^{[1
]}

Hong, Xuan ^{[4
]}

Goetz, Aaron ^{[2
]}

Stanley, Thomas ^{[3
]}

Taylor, J. David ^{[3
]}

Sigethy, Scott D. ^{[3
]}

Tomberlin, Ginger H. ^{[3
]}

Hassell, Annie M. ^{[4
]}

Kahler, Kirsten M. ^{[4
]}

Shewchuk, Lisa M. ^{[4
]}

Gampe, Robert T. ^{[4
]}

机构：

[1] GlaxoSmithKline Res & Dev Ltd, Prot Dynam DPU, Oncol Res, Collegeville, PA 19426 USA

[2] GlaxoSmithKline Res & Dev Ltd, Screening & Compound Profiling, Res Triangle Pk, NC 27713 USA

[3] GlaxoSmithKline Res & Dev Ltd, Biol Reagents & Assay Dev, Res Triangle Pk, NC 27713 USA

[4] GlaxoSmithKline Res & Dev Ltd, Computat & Struct Chem, Res Triangle Pk, NC 27713 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 16期

关键词：

STRESS-RESPONSE; TRANSLATION; ACTIVATION; HYPOXIA; DESIGN; PEK;

D O I：

10.1021/jm300713s

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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.

引用

页码：7193 / 7207

页数：15

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