Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor

被引：73

作者：

Heffron, Timothy P. ^{[1
]}

Berry, Megan ^{[2
]}

Castanedo, Georgette ^{[1
]}

Chang, Christine ^{[3
]}

Chuckowree, Irina ^{[4
]}

Dotson, Jennafer ^{[1
]}

Folkes, Adrian ^{[4
]}

Gunzner, Janet ^{[1
]}

Lesnick, John D. ^{[3
]}

Lewis, Cristina ^{[3
]}

Mathieu, Simon ^{[1
]}

Nonomiya, Jim ^{[3
]}

Olivero, Alan ^{[1
]}

Pang, Jodie ^{[5
]}

Peterson, David ^{[3
]}

Salphati, Laurent ^{[5
]}

Sampath, Deepak ^{[2
]}

Sideris, Steve ^{[3
]}

Sutherlin, Daniel P. ^{[1
]}

Tsui, Vickie ^{[1
]}

Wan, Nan Chi ^{[4
]}

Wang, Shumei ^{[1
]}

Wong, Susan ^{[5
]}

Zhu, Bing-yan ^{[1
]}

机构：

[1] Genentech Inc, Discovery Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Small Mol Translat Oncol, San Francisco, CA 94080 USA

[3] Genentech Inc, Biochem Pharmacol, San Francisco, CA 94080 USA

[4] Piramed Pharma, Slough SL1 4NL, Berks, England

[5] Genentech Inc, Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 08期

关键词：

PI3K; mTOR; Kinase inhibitors; CANCER; PATHWAY; MTOR;

D O I：

10.1016/j.bmcl.2010.03.046

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modi. cation resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2408 / 2411

页数：4

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