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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.

Original publication

DOI

10.1021/cb400430t

Type

Journal article

Journal

ACS Chem Biol

Publication Date

18/10/2013

Volume

8

Pages

2145 - 2150

Keywords

Cell Line, Tumor, Cell Proliferation, Crystallography, X-Ray, Discoidin Domain Receptor 1, Drug Discovery, Drug Screening Assays, Antitumor, Humans, Inhibitory Concentration 50, Models, Molecular, Neoplasms, Protein Kinase Inhibitors, Receptor Protein-Tyrosine Kinases