5bvk | pdb_00005bvk

Fragment-based discovery of potent and selective DDR1/2 inhibitors

spinqualitylabelsall models 5bvk, resolution 2.29Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5bvk is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 4VC, IOD Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the "back-to-front" design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments. Further optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2. The inhibitors were shown to potently inhibit DDR2 activity in cells but in contrast to unselective inhibitors such as dasatinib, they did not inhibit proliferation of mutant DDR2 lung SCC cell lines. Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.,Murray CW, Berdini V, Buck IM, Carr ME, Cleasby A, Coyle JE, Curry JE, Day JE, Day PJ, Hearn K, Iqbal A, Lee LY, Martins V, Mortenson PN, Munck JM, Page LW, Patel S, Roomans S, Smith K, Tamanini E, Saxty G ACS Med Chem Lett. 2015 Jun 4;6(7):798-803. doi: 10.1021/acsmedchemlett.5b00143. , eCollection 2015 Jul 9. PMID:26191369 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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