Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors
Peter Canning 1, Li Tan 2, Kiki Chu 3, Sam W Lee 3, Nathanael S Gray 4, Alex N Bullock 5
The discoidin domain receptors (DDRs), DDR1 and DDR2, form a distinctive subfamily of receptor tyrosine kinases which are activated through the binding of triple-helical bovine collagen. Excessive signaling by DDR1 and DDR2 continues to be from the advancement of various human illnesses, including fibrosis, coronary artery disease and cancer. We report the inhibition of those unusual receptor tyrosine kinases through the multi-targeted cancer drugs imatinib and ponatinib, along with the selective type II inhibitor DDR1-IN-1. Ponatinib is recognized as the greater potent molecule, which inhibits DDR1 and DDR2 by having an IC50 of 9nM. Co-very structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) from the kinase domain that’s stabilized by a unique salt bridge between your activation loop and |¨¢D helix. Variations to Abelson kinase (ABL) are noticed in the DDR1 P-loop, in which a |?-hairpin replaces the cage-like structure of ABL. P-loop residues in DDR1 that confer drug resistance in ABL are thus covered outdoors the ATP pocket. Whereas imatinib and ponatinib bind potently to both DDR and ABL kinases, the hydrophobic interactions from the ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural grounds for its DDR1 selectivity. Such inhibitors might have applications in clinical warning signs of DDR1 and DDR2 overexpression or mutation, including cancer of the lung.