6p5p - Revision history

OCA at 07:23, 11 October 2023

OCA — Wed, 11 Oct 2023 07:23:30 GMT

←Older revision		Revision as of 07:23, 11 October 2023
Line 3:		Line 3:
	<StructureSection load='6p5p' size='340' side='right'caption='[[6p5p]], [[Resolution\|resolution]] 3.30Å' scene=''>		<StructureSection load='6p5p' size='340' side='right'caption='[[6p5p]], [[Resolution\|resolution]] 3.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6p5p]] is a 4 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=6P5P OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6P5P FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6p5p]] is a 4 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=6P5P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6P5P FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O1V:2-[(2S)-1-azabicyclo[2.2.2]octan-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one'>O1V</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]] 3.3Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ROCK2, KIAA0619 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=O1V:2-[(2S)-1-azabicyclo[2.2.2]octan-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one'>O1V</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=6p5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p5p OCA], [https://pdbe.org/6p5p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6p5p RCSB], [https://www.ebi.ac.uk/pdbsum/6p5p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6p5p ProSAT]</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=6p5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p5p OCA], [~~http~~://pdbe.org/6p5p PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6p5p RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6p5p PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6p5p ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/ROCK2_HUMAN ROCK2_HUMAN]] Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus.<ref>PMID:10579722</ref> <ref>PMID:15699075</ref> <ref>PMID:16574662</ref> <ref>PMID:17015463</ref> <ref>PMID:19131646</ref> <ref>PMID:19997641</ref> <ref>PMID:21084279</ref> <ref>PMID:21147781</ref>	+	[https://www.uniprot.org/uniprot/ROCK2_HUMAN ROCK2_HUMAN] Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus.<ref>PMID:10579722</ref> <ref>PMID:15699075</ref> <ref>PMID:16574662</ref> <ref>PMID:17015463</ref> <ref>PMID:19131646</ref> <ref>PMID:19997641</ref> <ref>PMID:21084279</ref> <ref>PMID:21147781</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 20:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 6p5p" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6p5p" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Rho-associated protein kinase\|Rho-associated protein kinase]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific serine/threonine protein kinase]]~~	+	[[Category: Hoffman ID]]
-	[[Category: Hoffman~~, I D~~]]	+	[[Category: Skene RJ]]
-	[[Category: Skene~~, R J]]~~	+
-	~~[[Category: Anti-tumor]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Oral]]~~	+
-	~~[[Category: Transferase-transferase inhibitor]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 10:25, 26 February 2020

OCA — Wed, 26 Feb 2020 10:25:25 GMT

←Older revision		Revision as of 10:25, 26 February 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6p5p is ~~ON HOLD~~	+	==Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Anti-Tumor Agent==
		+	<StructureSection load='6p5p' size='340' side='right'caption='[[6p5p]], [[Resolution\|resolution]] 3.30Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6p5p]] is a 4 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=6P5P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P5P FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O1V:2-[(2S)-1-azabicyclo[2.2.2]octan-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one'>O1V</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ROCK2, KIAA0619 ([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/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=6p5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p5p OCA], [http://pdbe.org/6p5p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p5p RCSB], [http://www.ebi.ac.uk/pdbsum/6p5p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p5p ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/ROCK2_HUMAN ROCK2_HUMAN]] Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus.<ref>PMID:10579722</ref> <ref>PMID:15699075</ref> <ref>PMID:16574662</ref> <ref>PMID:17015463</ref> <ref>PMID:19131646</ref> <ref>PMID:19997641</ref> <ref>PMID:21084279</ref> <ref>PMID:21147781</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.

-	~~Authors: Hoffman~~, ~~I.D~~., ~~Skene~~, R.J.	+	Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent.,Kurasawa O, Miyazaki T, Homma M, Oguro Y, Imada T, Uchiyama N, Iwai K, Yamamoto Y, Ohori M, Hara H, Sugimoto H, Iwata K, Skene R, Hoffman I, Ohashi A, Nomura T, Cho N J Med Chem. 2020 Feb 13;63(3):1084-1104. doi: 10.1021/acs.jmedchem.9b01427. Epub , 2020 Jan 14. PMID:31895562<ref>PMID:31895562</ref>

-	~~Description: Discovery of a Novel~~, ~~Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 inhibitor with~~ a ~~Quinuclidine Moiety (TAK~~-~~931) as an Orally Active Investigational Anti~~-~~Tumor Agent~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: Hoffman, I.D]]	+	<div class="pdbe-citations 6p5p" style="background-color:#fffaf0;"></div>
-	[[Category: Skene, R.J]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Hoffman, I D]]
		+	[[Category: Skene, R J]]
		+	[[Category: Anti-tumor]]
		+	[[Category: Inhibitor]]
		+	[[Category: Kinase]]
		+	[[Category: Oral]]
		+	[[Category: Transferase-transferase inhibitor]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA: Protected "6p5p" [edit=sysop:move=sysop]

OCA — Wed, 12 Jun 2019 04:02:10 GMT

Protected "6p5p" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:02, 12 June 2019

OCA: New page: '''Unreleased structure''' The entry 6p5p is ON HOLD Authors: Hoffman, I.D., Skene, R.J. Description: Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based...

OCA — Wed, 12 Jun 2019 04:02:08 GMT

New page: '''Unreleased structure''' The entry 6p5p is ON HOLD Authors: Hoffman, I.D., Skene, R.J. Description: Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based...

New page

'''Unreleased structure'''

The entry 6p5p is ON HOLD

Authors: Hoffman, I.D., Skene, R.J.

Description: Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Anti-Tumor Agent
[[Category: Unreleased Structures]]
[[Category: Hoffman, I.D]]
[[Category: Skene, R.J]]