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==CRYSTAL STRUCTURE OF HUMAN MPS1 CATALYTIC DOMAIN IN COMPLEX WITH N-cyclopropyl-4-(8-((thiophen-2-ylmethyl)amino)imidazo[1,2-a]pyrazin-3-yl)benzamide== | ==CRYSTAL STRUCTURE OF HUMAN MPS1 CATALYTIC DOMAIN IN COMPLEX WITH N-cyclopropyl-4-(8-((thiophen-2-ylmethyl)amino)imidazo[1,2-a]pyrazin-3-yl)benzamide== | ||
<StructureSection load='3wzk' size='340' side='right'caption='[[3wzk]]' scene=''> | <StructureSection load='3wzk' size='340' side='right'caption='[[3wzk]], [[Resolution|resolution]] 2.30Å' 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=3WZK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WZK FirstGlance]. <br> | <table><tr><td colspan='2'>[[3wzk]] 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=3WZK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WZK FirstGlance]. <br> | ||
</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=3wzk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wzk OCA], [https://pdbe.org/3wzk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wzk RCSB], [https://www.ebi.ac.uk/pdbsum/3wzk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wzk ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=O23:N-CYCLOPROPYL-4-{8-[(THIOPHEN-2-YLMETHYL)AMINO]IMIDAZO[1,2-A]PYRAZIN-3-YL}BENZAMIDE'>O23</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=3wzk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wzk OCA], [https://pdbe.org/3wzk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wzk RCSB], [https://www.ebi.ac.uk/pdbsum/3wzk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wzk ProSAT]</span></td></tr> | |||
</table> | </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) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines. | |||
Discovery of Imidazo[1,2-b]pyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity.,Kusakabe KI, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Ando S, Maeda M, Higaki M, Baba Y, Nakamura Y J Med Chem. 2015 Feb 10. PMID:25625617<ref>PMID:25625617</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3wzk" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]] | *[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Ando S]] | [[Category: Ando S]] | ||