3k5u

Identification, SAR Studies and X-ray Cocrystal Analysis of a Novel Furano-pyrimidine Aurora Kinase A Inhibitor

spinqualitylabelsall models 3k5u, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3k5u is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.35Å Ligands: PFQ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AURKA_HUMAN Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and stabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity. Necessary for proper cilia disassembly prior to mitosis. Publication Abstract from PubMed Herein we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in-house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in-house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy, with IC(50) values ranging from approximately 300 nM to approximately 15 microM, by testing only 133 compounds from a database of approximately 125,000 compounds. Structure-activity relationship studies and X-ray co-crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC(50) value of 309 nM toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors. Identification, SAR studies, and X-ray co-crystallographic analysis of a novel furanopyrimidine aurora kinase A inhibitor.,Coumar MS, Tsai MT, Chu CY, Uang BJ, Lin WH, Chang CY, Chang TY, Leou JS, Teng CH, Wu JS, Fang MY, Chen CH, Hsu JT, Wu SY, Chao YS, Hsieh HP ChemMedChem. 2010 Feb 1;5(2):255-67. PMID:20039358 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase 3D structures

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