3w1f

Crystal structure of Human MPS1 catalytic domain in complex with 5-(5-ethoxy-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-2-methylbenzenesulfonamide

spinqualitylabelsall models 3w1f, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3w1f is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1O5 Related: 3vqu Gene: TTK, MPS1, MPS1L1 (HUMAN) Activity: Dual-specificity kinase, with EC number 2.7.12.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [TTK_HUMAN] Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint. Publication Abstract from PubMed Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively. Indazole-Based Potent and Cell-Active Mps1 Kinase Inhibitors: Rational Design from Pan-Kinase Inhibitor Anthrapyrazolone (SP600125).,Kusakabe K, Ide N, Daigo Y, Tachibana Y, Itoh T, Yamamoto T, Hashizume H, Hato Y, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Yasuo K, Maeda M, Higaki M, Ueda K, Yoshizawa H, Baba Y, Shiota T, Murai H, Nakamura Y J Med Chem. 2013 Jun 13;56(11):4343-56. doi: 10.1021/jm4000215. Epub 2013 May 24. PMID:23634759 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dual specificity protein kinase

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