Substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as multi-targeted inhibitors of insulin-like growth factor-1 receptor (IGF1R) and members of ErbB-family receptor kinases

被引：23

作者：

Wang, Gary T. ^{[1
]}

Mantei, Robert A. ^{[1
]}

Hubbard, Robert D. ^{[1
]}

Wilsbacher, Julie L. ^{[1
]}

Zhang, Qian ^{[1
]}

Tucker, Lora ^{[1
]}

Hu, Xiaoming ^{[1
]}

Kovar, Peter ^{[1
]}

Johnson, Eric F. ^{[1
]}

Osterling, Donald J. ^{[1
]}

Bouska, Jennifer ^{[1
]}

Wang, Jieyi ^{[1
]}

Davidsen, Steven K. ^{[1
]}

Bell, Randy L. ^{[1
]}

Sheppard, George S. ^{[1
]}

机构：

[1] Abbott Labs, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

来源：

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

关键词：

Multi-targeted kinase inhibitors; IGF1R; EGFR; ErbB2; ACQUIRED-RESISTANCE; ANTITUMOR-ACTIVITY; CANCER-CELLS; POTENT; DISCOVERY; LAPATINIB; ANTIBODY; BREAST;

D O I：

10.1016/j.bmcl.2010.08.052

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This Letter describes the lead discovery, optimization, and biological characterization of a series of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as potent inhibitors of IGF1R, EGFR, and ErbB2. The leading compound 11 showed an IGF1R IC50 of 12 nM, an EGFR (L858R) IC50 of 31 nM, and an ErbB2 IC50 of 11 nM, potent activity in cellular functional and anti-proliferation assays, as well as activity in an in vivo pharmacodynamic assay. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：6067 / 6071

页数：5

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