Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor
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- 作者：Hyung-Gu Kim ; Li Tan ; Ellen L. Weisberg ; Feiyang Liu ; Peter Canning ; Hwan Geun Choi ; Scott A. Ezell ; Hong Wu ; Zheng Zhao ; Jinhua Wang ; Anna Mandinova ; James D. Griffin ; Alex N. Bullock ; Qingsong Liu ; Sam W. Lee ; Nathanael S. Gray
- 刊名：ACS Chemical Biology
- 出版年：2013
- 出版时间：October 18, 2013
- 年：2013
- 卷：8
- 期：10
- 页码：2145-2150
- 全文大小：459K
- 年卷期：v.8,no.10(October 18, 2013)
- ISSN：1554-8937
文摘
The DDR1 receptor tyrosine kinase is activated by matrix collagens and has been implicated in numerous cellular functions such as proliferation, differentiation, adhesion, migration, and invasion. Here we report the discovery of a potent and selective DDR1 inhibitor, DDR1-IN-1, and present the 2.2 脜 DDR1 co-crystal structure. DDR1-IN-1 binds to DDR1 in the 鈥楧FG-out鈥?conformation and inhibits DDR1 autophosphorylation in cells at submicromolar concentrations with good selectivity as assessed against a panel of 451 kinases measured using the KinomeScan technology. We identified a mutation in the hinge region of DDR1, G707A, that confers >20-fold resistance to the ability of DDR1-IN-1 to inhibit DDR1 autophosphorylation and can be used to establish what pharmacology is DDR1-dependent. A combinatorial screen of DDR1-IN-1 with a library of annotated kinase inhibitors revealed that inhibitors of PI3K and mTOR such as GSK2126458 potentiate the antiproliferative activity of DDR1-IN-1 in colorectal cancer cell lines. DDR1-IN-1 provides a useful pharmacological probe for DDR1-dependent signal transduction.