View source for 5ei8


==Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 (MPS1) Using a Structure-Based Hydridization Approach==
<StructureSection load='5ei8' size='340' side='right'caption='[[5ei8]], [[Resolution|resolution]] 2.17&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ei8]] 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=5EI8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EI8 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.17&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5OE:~{N}-[2-METHOXY-4-(1-METHYLPYRAZOL-4-YL)PHENYL]-8-(1-METHYLPYRAZOL-4-YL)PYRIDO[3,4-D]PYRIMIDIN-2-AMINE'>5OE</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=5ei8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ei8 OCA], [https://pdbe.org/5ei8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ei8 RCSB], [https://www.ebi.ac.uk/pdbsum/5ei8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ei8 ProSAT]</span></td></tr>
</table>
== 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;">
== Publication Abstract from PubMed ==
Monopolar 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<ref>PMID:27055065</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ei8" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Baker R]]
[[Category: Blagg J]]
[[Category: Box G]]
[[Category: Burke R]]
[[Category: Cronin N]]
[[Category: De Haven Brandon A]]
[[Category: Eccles SA]]
[[Category: Faisal A]]
[[Category: Hayes A]]
[[Category: Henley AT]]
[[Category: Hoelder S]]
[[Category: Innocenti P]]
[[Category: Linardopoulos S]]
[[Category: Mak G]]
[[Category: Naud N]]
[[Category: O'Fee L]]
[[Category: Raymaud FI]]
[[Category: Roberts J]]
[[Category: Saville J]]
[[Category: Schmitt J]]
[[Category: Solanki S]]
[[Category: Valenti M]]
[[Category: Westwood IM]]
[[Category: Woodward HL]]
[[Category: Van Montfort RLM]]