Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin

被引：328

作者：

Knight, Steven D. ^{[1
]}

Adams, Nicholas D. ^{[1
]}

Burgess, JoeIle L. ^{[1
]}

Chaudhari, Amita M. ^{[1
]}

Darcy, Michael G. ^{[1
]}

Donatelli, Carla A. ^{[1
]}

Luengo, Juan I. ^{[1
]}

Newlander, Ken A. ^{[1
]}

Parrish, Cynthia A. ^{[1
]}

Ridgers, Lance H. ^{[1
]}

Sarpong, Martha A. ^{[1
]}

Schmidt, Stanley J. ^{[1
]}

Van Aller, Glenn S. ^{[1
]}

Carson, Jeffrey D. ^{[1
]}

Diamond, Melody A. ^{[1
]}

Elkins, Patricia A. ^{[1
]}

Gardiner, Christine M. ^{[1
]}

Garver, Eric ^{[1
]}

Gilbert, Seth A. ^{[1
]}

Gontarek, Richard R. ^{[1
]}

Jackson, Jeffrey R. ^{[1
]}

Kershner, Kevin L. ^{[1
]}

Luo, Lusong ^{[1
]}

Raha, Kaushik ^{[1
]}

Sherk, Christian S. ^{[1
]}

Sung, Chiu-Mei ^{[1
]}

Sutton, David ^{[1
]}

Tummino, Peter J. ^{[1
]}

Wegrzyn, Ronald J. ^{[1
]}

Auger, Kurt R. ^{[1
]}

Dhanak, Dashyant ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Collegeville, PA 19426 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2010年 / 1卷 / 01期

关键词：

GSK2126458; phosphoinositide 3-kinase alpha; mammalian target of rapamycin; PI3K/AKT pathway; CANCER-SPECIFIC MUTATIONS; PHOSPHATIDYLINOSITOL; 3-KINASES; PIK3CA; PHOSPHORYLATION; IDENTIFICATION; P110-ALPHA; PATHWAY; CELL;

D O I：

10.1021/ml900028r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Phosphomositide 3-kinase alpha (PI3K alpha) is a critical regulator of cell growth and transformation, and its signaling pathway is the most commonly mutated pathway in human cancers The mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, is also a central regulator of cell growth, and mTOR inhibitors are believed to augment the antiproliferative efficacy of PI3K/AKT pathway inhibition 2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK2126458, 1) has been identified as a highly potent, orally bioavailable inhibitor of PI3K alpha and mTOR with in vivo activity in both pharrnacodynamic and tumor growth efficacy models Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer.

引用

页码：39 / 43

页数：5

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