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Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor

DOI: 10.1021/cb400430t DOI Help
PMID: 23899692 PMID Help

Authors: Hyung-gu Kim (Massachusetts General Hospital and Harvard Medical School) , Li Tan (Harvard Medical School) , Ellen L. Weisberg (Harvard Medical School) , Feiyang Liu (Chinese Academy of Sciences) , Peter Canning (University of Oxford) , Hwan Geun Choi (Harvard Medical School) , Scott A. Ezell (Massachusetts General Hospital and Harvard Medical School) , Hong Wu (Chinese Academy of Sciences) , Zheng Zhao (Chinese Academy of Sciences) , Jinhua Wang (Harvard Medical School) , Anna Mandinova (Massachusetts General Hospital and Harvard Medical School) , James D. Griffin (Harvard Medical School) , Alex N. Bullock (University of Oxford) , Qingsong Liu (Chinese Academy of Sciences) , Sam W. Lee (Massachusetts General Hospital and Harvard Medical School) , Nathanael S. Gray (Harvard Medical School)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology , VOL 8 (10) , PAGES 2145 - 2150

State: Published (Approved)
Published: October 2013

Open Access Open Access

Abstract: 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 Å DDR1 co-crystal structure. DDR1-IN-1 binds to DDR1 in the ‘DFG-out’ 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.

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography