6tnc - Revision history

OCA at 07:38, 1 May 2024

OCA — Wed, 01 May 2024 07:38:42 GMT

←Older revision		Revision as of 07:38, 1 May 2024
Line 3:		Line 3:
	<StructureSection load='6tnc' size='340' side='right'caption='[[6tnc]], [[Resolution\|resolution]] 2.30Å' scene=''>		<StructureSection load='6tnc' size='340' side='right'caption='[[6tnc]], [[Resolution\|resolution]] 2.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6tnc]] 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=6TNC OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6TNC FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6tnc]] 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=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='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>~~	+	</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='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene~~></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='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='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>
-	<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=6tnc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tnc OCA], [~~http~~://pdbe.org/6tnc PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6tnc RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6tnc PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6tnc ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== 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>	+	[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 ==~~	+
-	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 6tnc" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 28:		Line 17:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Dual-specificity kinase]]~~	+	[[Category: Homo sapiens]]
-	~~[[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~~, S J~~]]	+	[[Category: Holton SJ]]
-	[[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~~, V K~~]]	+	[[Category: Schulze VK]]
-	[[Category: Siemeister, G]]	+	[[Category: Siemeister G]]
-	~~[[Category: Cell cycle]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Mps1~~]]	+

OCA at 11:31, 26 August 2020

OCA — Wed, 26 Aug 2020 11:31:55 GMT

←Older revision		Revision as of 11:31, 26 August 2020
Line 1:		Line 1:

	==X-RAY STRUCTURE OF MPS1 IN COMPLEX WITH COMPOUND 46==		==X-RAY STRUCTURE OF MPS1 IN COMPLEX WITH COMPOUND 46==
-	<StructureSection load='6tnc' size='340' side='right'caption='[[6tnc]]' scene=''>	+	<StructureSection load='6tnc' size='340' side='right'caption='[[6tnc]], [[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=6TNC OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TNC FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6tnc]] 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=6TNC OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TNC 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=6tnc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tnc OCA], [http://pdbe.org/6tnc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tnc RCSB], [http://www.ebi.ac.uk/pdbsum/6tnc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tnc 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=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='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=6tnc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tnc OCA], [http://pdbe.org/6tnc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tnc RCSB], [http://www.ebi.ac.uk/pdbsum/6tnc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tnc 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 6tnc" 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 SJ]]	+	[[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 VK]]	+	[[Category: Schulze, V K]]
-	[[Category: Siemeister G]]	+	[[Category: Siemeister, G]]
		+	[[Category: Cell cycle]]
		+	[[Category: Kinase]]
		+	[[Category: Mps1]]

OCA at 05:31, 13 May 2020

OCA — Wed, 13 May 2020 05:31:14 GMT

←Older revision		Revision as of 05:31, 13 May 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6tnc is ~~ON HOLD until Paper Publication~~	+	==X-RAY STRUCTURE OF MPS1 IN COMPLEX WITH COMPOUND 46==
-		+	<StructureSection load='6tnc' size='340' side='right'caption='[[6tnc]]' scene=''>
-	~~Authors~~:	+	== 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 [http://proteopedia.org/fgij/fg.htm?mol=6TNC FirstGlance]. <br>
-	~~Description~~:	+	</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=6tnc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tnc OCA], [http://pdbe.org/6tnc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tnc RCSB], [http://www.ebi.ac.uk/pdbsum/6tnc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tnc ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
		+	__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]]

OCA at 06:42, 1 January 2020

OCA — Wed, 01 Jan 2020 06:42:53 GMT

←Older revision		Revision as of 06:42, 1 January 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6tnc is ON HOLD	+	The entry 6tnc is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "6tnc" [edit=sysop:move=sysop]

OCA — Wed, 18 Dec 2019 05:51:30 GMT

Protected "6tnc" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:51, 18 December 2019

OCA: New page: '''Unreleased structure''' The entry 6tnc is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 18 Dec 2019 05:51:28 GMT

New page: '''Unreleased structure''' The entry 6tnc is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6tnc is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]