6tnd

X-RAY STRUCTURE OF MPS1 IN COMPLEX WITH COMPOUND 79

spinqualitylabelsall models 6tnd, resolution 2.58Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6tnd 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: 8RH 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 Inhibition of monopolar spindle 1 (MPS1) kinase represents a novel approach to cancer treatment: instead of arresting the cell cycle in tumor cells, cells are driven into mitosis irrespective of DNA damage and unattached/misattached chromosomes, resulting in aneuploidy and cell death. Starting points for our optimization efforts with the goal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series "triazolopyridines" and "imidazopyrazines". The major initial issue of the triazolopyridine series was the moderate potency of the HTS hits. The imidazopyrazine series displayed more than 10-fold higher potencies; however, in the early project phase, this series suffered from poor metabolic stability. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of MPS1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy models. Treating Cancer by Spindle Assembly Checkpoint Abrogation: Discovery of Two Clinical Candidates, BAY 1161909 and BAY 1217389, Targeting MPS1 Kinase.,Schulze VK, Klar U, Kosemund D, Wengner AM, Siemeister G, Stockigt D, Neuhaus R, Lienau P, Bader B, Prechtl S, Holton SJ, Briem H, Marquardt T, Schirok H, Jautelat R, Bohlmann R, Nguyen D, Fernandez-Montalvan AE, Bomer U, Eberspaecher U, Bruning M, Dohr O, Raschke M, Kreft B, Mumberg D, Ziegelbauer K, Brands M, von Nussbaum F, Koppitz M J Med Chem. 2020 Apr 27. doi: 10.1021/acs.jmedchem.9b02035. PMID:32338514 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dual specificity protein kinase 3D structures

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