View source for 6tnc


==X-RAY STRUCTURE OF MPS1 IN COMPLEX WITH COMPOUND 46==
<StructureSection load='6tnc' size='340' side='right'caption='[[6tnc]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TNC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TNC 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]] 2.3&#8491;</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>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=6tnc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tnc OCA], [https://pdbe.org/6tnc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tnc RCSB], [https://www.ebi.ac.uk/pdbsum/6tnc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tnc ProSAT]</span></td></tr>
</table>
<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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6tnc" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Bader B]]
[[Category: Boemer U]]
[[Category: Bohlmann R]]
[[Category: Brands M]]
[[Category: Briem H]]
[[Category: Eberspaecher U]]
[[Category: Fernandez-Montalvan A]]
[[Category: Holton SJ]]
[[Category: Klar U]]
[[Category: Koppitz M]]
[[Category: Kosemund D]]
[[Category: Marquardt T]]
[[Category: Nguyen D]]
[[Category: Nussbaum F]]
[[Category: Prechtl S]]
[[Category: Schirok H]]
[[Category: Schulze VK]]
[[Category: Siemeister G]]