title: Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor.
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.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School , Charlestown, Massachusetts 02129, United States.
authors.forename: Hyung-Gu
authors.initials: HG
authors.lastname: Kim
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Weisberg
authors.forename: Feiyang
authors.initials: F
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Canning
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Scott A
authors.initials: SA
authors.lastname: Ezell
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Anna
authors.initials: A
authors.lastname: Mandinova
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D000070819:Discoidin Domain Receptor 1; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases
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