6gwr

Structure of the kinase domain of human DDR1 in complex with a potent and selective inhibitor of DDR1 and DDR2

spinqualitylabelsall models 6gwr, resolution 2.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6gwr is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, FEW, SO4 Gene: DDR1, CAK, EDDR1, NEP, NTRK4, PTK3A, RTK6, TRKE (HUMAN) Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Discoidin domain receptor 1 and 2 (DDR1 and DDR2) are new potential targets for anti-inflammatory drug discovery. A series of heterocycloalkynylbenzimides were designed and optimized to co-inhibit DDR1 and DDR2. One of the most promising compounds, 5n, tightly bound to DDR1 and DDR2 protein with Kd values of 7.9 and 8.0 nM, and potently inhibited the kinases with IC50 values of 9.4 and 20.4 nM, respectively, while was significantly less potent for a panel of 403 wild-type kinases at 1.0 muM. DDR1 and DDR2 kinase inhibition by 5n was validated by Western blotting analysis in primary human lung fibroblasts. The compound also dose-dependently inhibited lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) release in vitro, and exhibited promising in vivo anti-inflammatory effect in a LPS-induced acute lung injury (ALI) mouse model. Compound 5n may serve as a lead compound for new anti-inflammatory drug discovery. Design, Synthesis and Biological Evaluation of 3-(Imidazo[1,2-a]pyrazin-3-ylethynyl)-4-isopropyl-N-(3-((4-methylpiperazin-1-yl)m ethyl)-5-(trifluoromethyl)phenyl)benzamide as Dual Inhibitors of Discoidin Domain Receptor 1 and 2 (DDR1/2).,Wang Z, Zhang Y, Pinkas D, Fox A, Luo J, Huang H, Cui S, Xiang Q, Xu T, Xun Q, Zhu D, Tu ZC, Ren X, Brekken RA, Bullock AN, Liang G, Ding K, Lu X J Med Chem. 2018 Aug 3. doi: 10.1021/acs.jmedchem.8b01045. PMID:30075624 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA