5k3y

Crystal structure of AuroraB/INCENP in complex with BI 811283

spinqualitylabelsall models 5k3y, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5k3y is a 4 chain structure with sequence from Xenopus laevis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: 6Q4, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS-mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases (AK). Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays. Equipotent effects were observed in BRAF-mutant cells, while in KRAS-mutant cells, MEK inhibition required higher concentrations than AK inhibition. Daily oral administration of BI 847325 at 10 mg/kg showed efficacy in both BRAF- and KRAS-mutant xenograft models. Biomarker analysis suggested that this effect was primarily due to inhibition of MEK in BRAF mutant models, but of AK in KRAS-mutant models. Inhibition of both MEK and AK in KRAS-mutant tumors was observed when BI 847325 was administered once weekly at 70 mg/kg. Our studies indicate that BI 847325 is effective in in vitro and in vivo models of cancers with BRAF and KRAS mutation. These preclinical data are discussed in the light of the results of a recently completed clinical phase I trial assessing safety, tolerability, pharmacokinetics and efficacy of BI 847325 in cancer patients. Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-competitive Inhibitor of MEK and Aurora Kinases.,Sini P, Gurtler U, Zahn SK, Baumann C, Rudolph D, Baumgartinger R, Strauss E, Haslinger C, Tontsch-Grunt U, Waizenegger IC, Solca F, Bader G, Zoephel A, Treu M, Reiser U, Garin-Chesa P, Boehmelt G, Kraut N, Quant J, Adolf GR Mol Cancer Ther. 2016 Aug 5. pii: molcanther.0066.2016. PMID:27496137 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Centromere protein 3D structure Serine/threonine protein kinase 3D structures

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