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<StructureSection load='5eh0' size='340' side='right'caption='[[5eh0]], [[Resolution|resolution]] 2.18Å' scene=''> | <StructureSection load='5eh0' size='340' side='right'caption='[[5eh0]], [[Resolution|resolution]] 2.18Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5eh0]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[5eh0]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EH0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EH0 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5NW:N2-(2-METHOXY-4-(1-METHYL-1H-PYRAZOL-4-YL)PHENYL)-N8-NEOPENTYLPYRIDO[3,4-D]PYRIMIDINE-2,8-DIAMINE'>5NW</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.18Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5NW:N2-(2-METHOXY-4-(1-METHYL-1H-PYRAZOL-4-YL)PHENYL)-N8-NEOPENTYLPYRIDO[3,4-D]PYRIMIDINE-2,8-DIAMINE'>5NW</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5eh0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eh0 OCA], [https://pdbe.org/5eh0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5eh0 RCSB], [https://www.ebi.ac.uk/pdbsum/5eh0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5eh0 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 22: | Line 21: | ||
==See Also== | ==See Also== | ||
*[[Dual specificity protein kinase|Dual specificity protein kinase]] | *[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Baker R]] | |||
[[Category: Baker | [[Category: Blagg J]] | ||
[[Category: Blagg | [[Category: Box G]] | ||
[[Category: Box | [[Category: Burke R]] | ||
[[Category: Cronin N]] | |||
[[Category: Burke | [[Category: De Haven Brandon A]] | ||
[[Category: Cronin | [[Category: Eccles SA]] | ||
[[Category: | [[Category: Faisal A]] | ||
[[Category: | [[Category: Hayes A]] | ||
[[Category: | [[Category: Henley AT]] | ||
[[Category: Hayes | [[Category: Hoelder S]] | ||
[[Category: Henley | [[Category: Innocenti P]] | ||
[[Category: Hoelder | [[Category: Linardopoulos S]] | ||
[[Category: Innocenti | [[Category: Mak G]] | ||
[[Category: Linardopoulos | [[Category: Naud N]] | ||
[[Category: Mak | [[Category: O'Fee L]] | ||
[[Category: | [[Category: Raymaud FI]] | ||
[[Category: | [[Category: Roberts J]] | ||
[[Category: Raymaud | [[Category: Saville J]] | ||
[[Category: Roberts | [[Category: Schmitt J]] | ||
[[Category: Saville | [[Category: Solanki S]] | ||
[[Category: Schmitt | [[Category: Valenti M]] | ||
[[Category: Solanki | [[Category: Westwood IM]] | ||
[[Category: Valenti | [[Category: Woodward HL]] | ||
[[Category: Westwood | [[Category: Van Montfort RLM]] | ||
[[Category: Woodward | |||
[[Category: | |||
Latest revision as of 09:26, 5 July 2023
Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 (MPS1) Using a Structure-Based Hydridization ApproachRapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 (MPS1) Using a Structure-Based Hydridization Approach
Structural highlights
FunctionTTK_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 PubMedMonopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model. Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.,Innocenti P, Woodward HL, Solanki S, Naud S, Westwood IM, Cronin N, Hayes A, Roberts J, Henley AT, Baker R, Faisal A, Mak GW, Box G, Valenti M, De Haven Brandon A, O'Fee L, Saville H, Schmitt J, Matijssen B, Burke R, van Montfort RL, Raynaud FI, Eccles SA, Linardopoulos S, Blagg J, Hoelder S J Med Chem. 2016 Apr 28;59(8):3671-88. doi: 10.1021/acs.jmedchem.5b01811. Epub, 2016 Apr 7. PMID:27055065[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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