Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development

被引：184

作者：

Axten, Jeffrey M. ^{[1
]}

Romeril, Stuart P. ^{[1
]}

Shu, Arthur ^{[1
]}

Ralph, Jeffrey ^{[1
]}

Medina, Jesus R. ^{[1
]}

Feng, Yanhong ^{[1
]}

Li, William Hoi Hong ^{[1
]}

Grant, Seth W. ^{[1
]}

Heerding, Dirk A. ^{[1
]}

Minthorn, Elisabeth ^{[1
]}

Mencken, Thomas ^{[1
]}

Gaul, Nathan ^{[2
]}

Goetz, Aaron ^{[3
]}

Stanley, Thomas ^{[3
]}

Hassell, Annie M. ^{[4
]}

Gampe, Robert T. ^{[4
]}

Atkins, Charity ^{[1
]}

Kumar, Rakesh ^{[1
]}

机构：

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

[2] GlaxoSmithKline Res & Dev Ltd, Screening & Compound Profiling, Collegeville, PA 19426 USA

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

[4] GlaxoSmithKline Res & Dev Ltd, Biomol Struct Computat & Struct Chem, Res Triangle Pk, NC 27709 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 10期

关键词：

PERK; UPR; kinase; lead optimization; structure-activity relationship; fluorine interaction; UNFOLDED PROTEIN RESPONSE; TRANSLATIONAL CONTROL; KINASE PERK; STRESS; PANCREAS; FLUORINE; PATHWAY; GROWTH;

D O I：

10.1021/ml400228e

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：

We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasrnic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

引用

页码：964 / 968

页数：5

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