4c4i - Revision history

OCA at 12:03, 20 December 2023

OCA — Wed, 20 Dec 2023 12:03:33 GMT

←Older revision		Revision as of 12:03, 20 December 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4c4i]] 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=4C4I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C4I FirstGlance]. <br>		<table><tr><td colspan='2'>[[4c4i]] 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=4C4I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C4I FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=X20:TERT-BUTYL+6-{[2-CHLORO-4-(DIMETHYLCARBAMOYL)PHENYL]AMINO}-2-(1,3-OXAZOL-5-YL)-1H-PYRROLO[3,2-C]PYRIDINE-1-CARBOXYLATE'>X20</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]] 2.65Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=X20:TERT-BUTYL+6-{[2-CHLORO-4-(DIMETHYLCARBAMOYL)PHENYL]AMINO}-2-(1,3-OXAZOL-5-YL)-1H-PYRROLO[3,2-C]PYRIDINE-1-CARBOXYLATE'>X20</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=4c4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4i OCA], [https://pdbe.org/4c4i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c4i RCSB], [https://www.ebi.ac.uk/pdbsum/4c4i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c4i ProSAT]</span></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=4c4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4i OCA], [https://pdbe.org/4c4i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c4i RCSB], [https://www.ebi.ac.uk/pdbsum/4c4i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c4i ProSAT]</span></td></tr>
	</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>	+	[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 ==
		+	The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.
		+
		+	Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1).,Naud S, Westwood IM, Faisal A, Sheldrake P, Bavetsias V, Atrash B, Cheung KM, Liu M, Hayes A, Schmitt J, Wood A, Choi V, Boxall K, Mak G, Gurden M, Valenti M, de Haven Brandon A, Henley A, Baker R, McAndrew C, Matijssen B, Burke R, Hoelder S, Eccles SA, Raynaud FI, Linardopoulos S, van Montfort RL, Blagg J J Med Chem. 2013 Dec 2. PMID:24256217<ref>PMID:24256217</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 4c4i" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 17:26, 7 September 2022

OCA — Wed, 07 Sep 2022 17:26:38 GMT

←Older revision		Revision as of 17:26, 7 September 2022
Line 3:		Line 3:
	<StructureSection load='4c4i' size='340' side='right'caption='[[4c4i]], [[Resolution\|resolution]] 2.65Å' scene=''>		<StructureSection load='4c4i' size='340' side='right'caption='[[4c4i]], [[Resolution\|resolution]] 2.65Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4c4i]] 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=4C4I OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4C4I FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4c4i]] 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=4C4I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C4I FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=X20:TERT-BUTYL+6-{[2-CHLORO-4-(DIMETHYLCARBAMOYL)PHENYL]AMINO}-2-(1,3-OXAZOL-5-YL)-1H-PYRROLO[3,2-C]PYRIDINE-1-CARBOXYLATE'>X20</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=X20:TERT-BUTYL+6-{[2-CHLORO-4-(DIMETHYLCARBAMOYL)PHENYL]AMINO}-2-(1,3-OXAZOL-5-YL)-1H-PYRROLO[3,2-C]PYRIDINE-1-CARBOXYLATE'>X20</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4c4e\|4c4e]], [[4c4f\|4c4f]], [[4c4g\|4c4g]], [[4c4h\|4c4h]], [[4c4j\|4c4j]]</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=4c4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4i OCA], [https://pdbe.org/4c4i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c4i RCSB], [https://www.ebi.ac.uk/pdbsum/4c4i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c4i 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~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4c4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4i OCA], [~~http~~://pdbe.org/4c4i PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4c4i RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4c4i PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4c4i 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 ==~~	+
-	The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.	+
-		+
-	Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1).,Naud S, Westwood IM, Faisal A, Sheldrake P, Bavetsias V, Atrash B, Cheung KM, Liu M, Hayes A, Schmitt J, Wood A, Choi V, Boxall K, Mak G, Gurden M, Valenti M, de Haven Brandon A, Henley A, Baker R, McAndrew C, Matijssen B, Burke R, Hoelder S, Eccles SA, Raynaud FI, Linardopoulos S, van Montfort RL, Blagg J J Med Chem. 2013 Dec 2. PMID:24256217<ref>PMID:24256217</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 4c4i" style="background-color:#fffaf0;"></div~~>	+

	==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: ~~Dual-specificity kinase]]~~	+	[[Category: Homo sapiens]]
-	~~[[Category: Human~~]]	+
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Atrash, B]]	+	[[Category: Atrash B]]
-	[[Category: Baker, R]]	+	[[Category: Baker R]]
-	[[Category: Bavetsias, V]]	+	[[Category: Bavetsias V]]
-	[[Category: Blagg, J]]	+	[[Category: Blagg J]]
-	[[Category: Boxall, K]]	+	[[Category: Boxall K]]
-	~~[[Category: Brandon, A de Haven~~]]	+	[[Category: Burke R]]
-	[[Category: Burke, R]]	+	[[Category: Choi V]]
-	[[Category: Choi, V]]	+	[[Category: Eccles SA]]
-	[[Category: Eccles~~, S A~~]]	+	[[Category: Faisal A]]
-	[[Category: Faisal, A]]	+	[[Category: Gurden M]]
-	[[Category: Gurden, M]]	+	[[Category: Hayes A]]
-	[[Category: Hayes, A]]	+	[[Category: Henley A]]
-	[[Category: Henley, A]]	+	[[Category: Linardopoulos S]]
-	[[Category: Linardopoulos, S]]	+	[[Category: Liu M]]
-	[[Category: Liu, M]]	+	[[Category: Mak G]]
-	[[Category: Mak, G]]	+	[[Category: Matijssen B]]
-	[[Category: Matijssen, B]]	+	[[Category: McAndrew C]]
-	[[Category: McAndrew, C]]	+	[[Category: Naud S]]
-	~~[[Category: Montfort, R van~~]]	+	[[Category: Raynaud FI]]
-	[[Category: Naud, S]]	+	[[Category: Schmitt J]]
-	[[Category: Raynaud~~, F I~~]]	+	[[Category: Sheldrake P]]
-	[[Category: Schmitt, J]]	+	[[Category: Valenti M]]
-	[[Category: Sheldrake, P]]	+	[[Category: Westwood IM]]
-	[[Category: Valenti, M]]	+	[[Category: Wood A]]
-	[[Category: Westwood~~, I M~~]]	+	[[Category: De Haven Brandon A]]
-	[[Category: Wood, A]]	+	[[Category: Van Montfort R]]
-	[[Category: ~~Mitosis~~]]	+
-	[[Category: ~~Structure-based drug design]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 09:49, 20 March 2019

OCA — Wed, 20 Mar 2019 09:49:56 GMT

←Older revision		Revision as of 09:49, 20 March 2019
Line 1:		Line 1:

	==Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1==		==Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1==
-	<StructureSection load='4c4i' size='340' side='right' caption='[[4c4i]], [[Resolution\|resolution]] 2.65Å' scene=''>	+	<StructureSection load='4c4i' size='340' side='right'caption='[[4c4i]], [[Resolution\|resolution]] 2.65Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4c4i]] 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=4C4I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C4I FirstGlance]. <br>		<table><tr><td colspan='2'>[[4c4i]] 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=4C4I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C4I FirstGlance]. <br>
Line 29:		Line 29:
	[[Category: Dual-specificity kinase]]		[[Category: Dual-specificity kinase]]
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Atrash, B]]		[[Category: Atrash, B]]
	[[Category: Baker, R]]		[[Category: Baker, R]]

OCA at 16:39, 4 August 2016

OCA — Thu, 04 Aug 2016 16:39:13 GMT

←Older revision		Revision as of 16:39, 4 August 2016
Line 1:		Line 1:
		+
	==Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1==		==Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1==
	<StructureSection load='4c4i' size='340' side='right' caption='[[4c4i]], [[Resolution\|resolution]] 2.65Å' scene=''>		<StructureSection load='4c4i' size='340' side='right' caption='[[4c4i]], [[Resolution\|resolution]] 2.65Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4c4e\|4c4e]], [[4c4f\|4c4f]], [[4c4g\|4c4g]], [[4c4h\|4c4h]], [[4c4j\|4c4j]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4c4e\|4c4e]], [[4c4f\|4c4f]], [[4c4g\|4c4g]], [[4c4h\|4c4h]], [[4c4j\|4c4j]]</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='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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c4i RCSB], [http://www.ebi.ac.uk/pdbsum/4c4i PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4i OCA], [http://pdbe.org/4c4i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4c4i RCSB], [http://www.ebi.ac.uk/pdbsum/4c4i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4c4i ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4c4i" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 11:03, 25 December 2014

OCA — Thu, 25 Dec 2014 11:03:44 GMT

←Older revision		Revision as of 11:03, 25 December 2014
Line 8:		Line 8:
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c4i RCSB], [http://www.ebi.ac.uk/pdbsum/4c4i PDBsum]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c4i RCSB], [http://www.ebi.ac.uk/pdbsum/4c4i PDBsum]</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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 18:48, 21 December 2014

OCA — Sun, 21 Dec 2014 18:48:31 GMT

←Older revision		Revision as of 18:48, 21 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4c4i\| PDB=4c4i \| SCENE= }}~~	+	==Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1==
-	===Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1===	+	<StructureSection load='4c4i' size='340' side='right' caption='[[4c4i]], [[Resolution\|resolution]] 2.65Å' scene=''>
-	{~~{ABSTRACT_PUBMED_24256217}~~}	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4c4i]] 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=4C4I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C4I FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=X20:TERT-BUTYL+6-{[2-CHLORO-4-(DIMETHYLCARBAMOYL)PHENYL]AMINO}-2-(1,3-OXAZOL-5-YL)-1H-PYRROLO[3,2-C]PYRIDINE-1-CARBOXYLATE'>X20</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4c4e\|4c4e]], [[4c4f\|4c4f]], [[4c4g\|4c4g]], [[4c4h\|4c4h]], [[4c4j\|4c4j]]</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c4i RCSB], [http://www.ebi.ac.uk/pdbsum/4c4i PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.

-	~~==Function==~~	+	Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1).,Naud S, Westwood IM, Faisal A, Sheldrake P, Bavetsias V, Atrash B, Cheung KM, Liu M, Hayes A, Schmitt J, Wood A, Choi V, Boxall K, Mak G, Gurden M, Valenti M, de Haven Brandon A, Henley A, Baker R, McAndrew C, Matijssen B, Burke R, Hoelder S, Eccles SA, Raynaud FI, Linardopoulos S, van Montfort RL, Blagg J J Med Chem. 2013 Dec 2. PMID:24256217<ref>PMID:24256217</ref>
-	[~~[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>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4c4i]] 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=4C4I OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:024256217</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Dual specificity protein kinase\|Dual specificity protein kinase]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Dual-specificity kinase]]		[[Category: Dual-specificity kinase]]
	[[Category: Human]]		[[Category: Human]]
-	[[Category: Atrash, B.]]	+	[[Category: Atrash, B]]
-	[[Category: Baker, R.]]	+	[[Category: Baker, R]]
-	[[Category: Bavetsias, V.]]	+	[[Category: Bavetsias, V]]
-	[[Category: Blagg, J.]]	+	[[Category: Blagg, J]]
-	[[Category: Boxall, K.]]	+	[[Category: Boxall, K]]
-	[[Category: Brandon, A de Haven.]]	+	[[Category: Brandon, A de Haven]]
-	[[Category: Burke, R.]]	+	[[Category: Burke, R]]
-	[[Category: Choi, V.]]	+	[[Category: Choi, V]]
-	[[Category: Eccles, S A.]]	+	[[Category: Eccles, S A]]
-	[[Category: Faisal, A.]]	+	[[Category: Faisal, A]]
-	[[Category: Gurden, M.]]	+	[[Category: Gurden, M]]
-	[[Category: Hayes, A.]]	+	[[Category: Hayes, A]]
-	[[Category: Henley, A.]]	+	[[Category: Henley, A]]
-	[[Category: Linardopoulos, S.]]	+	[[Category: Linardopoulos, S]]
-	[[Category: Liu, M.]]	+	[[Category: Liu, M]]
-	[[Category: Mak, G.]]	+	[[Category: Mak, G]]
-	[[Category: Matijssen, B.]]	+	[[Category: Matijssen, B]]
-	[[Category: McAndrew, C.]]	+	[[Category: McAndrew, C]]
-	[[Category: Montfort, R van.]]	+	[[Category: Montfort, R van]]
-	[[Category: Naud, S.]]	+	[[Category: Naud, S]]
-	[[Category: Raynaud, F I.]]	+	[[Category: Raynaud, F I]]
-	[[Category: Schmitt, J.]]	+	[[Category: Schmitt, J]]
-	[[Category: Sheldrake, P.]]	+	[[Category: Sheldrake, P]]
-	[[Category: Valenti, M.]]	+	[[Category: Valenti, M]]
-	[[Category: Westwood, I M.]]	+	[[Category: Westwood, I M]]
-	[[Category: Wood, A.]]	+	[[Category: Wood, A]]
	[[Category: Mitosis]]		[[Category: Mitosis]]
	[[Category: Structure-based drug design]]		[[Category: Structure-based drug design]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 07:07, 15 January 2014

OCA — Wed, 15 Jan 2014 07:07:35 GMT

←Older revision		Revision as of 07:07, 15 January 2014
Line 7:		Line 7:

	==About this Structure==		==About this Structure==
-	[[4c4i]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C4I OCA].	+	[[4c4i]] 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=4C4I OCA].

	==Reference==		==Reference==
	<ref group="xtra">PMID:024256217</ref><references group="xtra"/><references/>		<ref group="xtra">PMID:024256217</ref><references group="xtra"/><references/>
	[[Category: Dual-specificity kinase]]		[[Category: Dual-specificity kinase]]
		+	[[Category: Human]]
	[[Category: Atrash, B.]]		[[Category: Atrash, B.]]
	[[Category: Baker, R.]]		[[Category: Baker, R.]]

OCA at 07:22, 4 December 2013

OCA — Wed, 04 Dec 2013 07:22:01 GMT

←Older revision		Revision as of 07:22, 4 December 2013
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	{{STRUCTURE_4c4i\| PDB=4c4i \| SCENE= }}
		+	===Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1===
		+	{{ABSTRACT_PUBMED_24256217}}

-	~~The entry 4c4i is ON HOLD~~ ~~until Paper Publication~~	+	==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>

-	~~Authors~~: Naud, S., Westwood, I.M., Faisal, A., Sheldrake, P., Bavetsias, V., Atrash, B., Liu, M., Hayes, A., Schmitt, J., Wood, A., Choi, V., Boxall, K., Mak, G., Gurden, M., Valenti, M., de Haven Brandon, A., Henley, A., Baker, R., McAndrew, C., Matijssen, B., Burke, R., Eccles, S.A., Raynaud, F.I.~~, Linardopoulos, S~~.~~, van Montfort, R~~.~~, Blagg, J~~.	+	==About this Structure==
		+	[[4c4i]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C4I OCA].

-	~~Description~~: Structure-based design ~~of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1~~	+	==Reference==
		+	<ref group="xtra">PMID:024256217</ref><references group="xtra"/><references/>
		+	[[Category: Dual-specificity kinase]]
		+	[[Category: Atrash, B.]]
		+	[[Category: Baker, R.]]
		+	[[Category: Bavetsias, V.]]
		+	[[Category: Blagg, J.]]
		+	[[Category: Boxall, K.]]
		+	[[Category: Brandon, A de Haven.]]
		+	[[Category: Burke, R.]]
		+	[[Category: Choi, V.]]
		+	[[Category: Eccles, S A.]]
		+	[[Category: Faisal, A.]]
		+	[[Category: Gurden, M.]]
		+	[[Category: Hayes, A.]]
		+	[[Category: Henley, A.]]
		+	[[Category: Linardopoulos, S.]]
		+	[[Category: Liu, M.]]
		+	[[Category: Mak, G.]]
		+	[[Category: Matijssen, B.]]
		+	[[Category: McAndrew, C.]]
		+	[[Category: Montfort, R van.]]
		+	[[Category: Naud, S.]]
		+	[[Category: Raynaud, F I.]]
		+	[[Category: Schmitt, J.]]
		+	[[Category: Sheldrake, P.]]
		+	[[Category: Valenti, M.]]
		+	[[Category: Westwood, I M.]]
		+	[[Category: Wood, A.]]
		+	[[Category: Mitosis]]
		+	[[Category: Structure-based drug design]]
		+	[[Category: Transferase]]

OCA at 03:17, 20 September 2013

OCA — Fri, 20 Sep 2013 03:17:48 GMT

←Older revision		Revision as of 03:17, 20 September 2013
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4c4i is ON HOLD	+	The entry 4c4i is ON HOLD until Paper Publication

	Authors: Naud, S., Westwood, I.M., Faisal, A., Sheldrake, P., Bavetsias, V., Atrash, B., Liu, M., Hayes, A., Schmitt, J., Wood, A., Choi, V., Boxall, K., Mak, G., Gurden, M., Valenti, M., de Haven Brandon, A., Henley, A., Baker, R., McAndrew, C., Matijssen, B., Burke, R., Eccles, S.A., Raynaud, F.I., Linardopoulos, S., van Montfort, R., Blagg, J.		Authors: Naud, S., Westwood, I.M., Faisal, A., Sheldrake, P., Bavetsias, V., Atrash, B., Liu, M., Hayes, A., Schmitt, J., Wood, A., Choi, V., Boxall, K., Mak, G., Gurden, M., Valenti, M., de Haven Brandon, A., Henley, A., Baker, R., McAndrew, C., Matijssen, B., Burke, R., Eccles, S.A., Raynaud, F.I., Linardopoulos, S., van Montfort, R., Blagg, J.

	Description: Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1		Description: Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1

OCA: Protected "4c4i" [edit=sysop:move=sysop]

OCA — Thu, 12 Sep 2013 04:31:11 GMT

Protected "4c4i" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:31, 12 September 2013