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==X-RAY STRUCTURE OF MPS1 IN COMPLEX WITH COMPOUND 16== | ==X-RAY STRUCTURE OF MPS1 IN COMPLEX WITH COMPOUND 16== | ||
<StructureSection load='6tn9' size='340' side='right'caption='[[6tn9]]' scene=''> | <StructureSection load='6tn9' size='340' side='right'caption='[[6tn9]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TN9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TN9 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6tn9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TN9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TN9 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6tn9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tn9 OCA], [http://pdbe.org/6tn9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tn9 RCSB], [http://www.ebi.ac.uk/pdbsum/6tn9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tn9 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NN5:[4-[[6-(3,5-dimethyl-4-oxidanyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]phenyl]-morpholin-4-yl-methanone'>NN5</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TTK, MPS1, MPS1L1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6tn9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tn9 OCA], [http://pdbe.org/6tn9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tn9 RCSB], [http://www.ebi.ac.uk/pdbsum/6tn9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tn9 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/TTK_HUMAN 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.<ref>PMID:18243099</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:32338514</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6tn9" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Dual-specificity kinase]] | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Bader B]] | [[Category: Bader, B]] | ||
[[Category: Boemer U]] | [[Category: Boemer, U]] | ||
[[Category: Bohlmann R]] | [[Category: Bohlmann, R]] | ||
[[Category: Brands M]] | [[Category: Brands, M]] | ||
[[Category: Briem H]] | [[Category: Briem, H]] | ||
[[Category: Eberspaecher U]] | [[Category: Eberspaecher, U]] | ||
[[Category: Fernandez-Montalvan A]] | [[Category: Fernandez-Montalvan, A]] | ||
[[Category: Holton | [[Category: Holton, S J]] | ||
[[Category: Klar U]] | [[Category: Klar, U]] | ||
[[Category: Koppitz M]] | [[Category: Koppitz, M]] | ||
[[Category: Kosemund D]] | [[Category: Kosemund, D]] | ||
[[Category: Marquardt T]] | [[Category: Marquardt, T]] | ||
[[Category: Nguyen D]] | [[Category: Nguyen, D]] | ||
[[Category: Nussbaum F]] | [[Category: Nussbaum, F]] | ||
[[Category: Prechtl S]] | [[Category: Prechtl, S]] | ||
[[Category: Schirok H]] | [[Category: Schirok, H]] | ||
[[Category: Schulze | [[Category: Schulze, V K]] | ||
[[Category: Siemeister G]] | [[Category: Siemeister, G]] | ||
[[Category: Cell cycle]] | |||
[[Category: Kinase]] | |||
[[Category: Mps1]] | |||
Revision as of 14:31, 26 August 2020
X-RAY STRUCTURE OF MPS1 IN COMPLEX WITH COMPOUND 16X-RAY STRUCTURE OF MPS1 IN COMPLEX WITH COMPOUND 16
Structural highlights
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.[1] Publication Abstract from PubMedInhibition 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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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