6p5m

From Proteopedia

(Difference between revisions)

Current revision

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

Structural highlights

6p5m is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.65Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

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.

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^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kawano Y, Fukata Y, Oshiro N, Amano M, Nakamura T, Ito M, Matsumura F, Inagaki M, Kaibuchi K. Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo. J Cell Biol. 1999 Nov 29;147(5):1023-38. PMID:10579722
↑ Sebbagh M, Hamelin J, Bertoglio J, Solary E, Breard J. Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner. J Exp Med. 2005 Feb 7;201(3):465-71. PMID:15699075 doi:10.1084/jem.20031877
↑ Tanaka T, Nishimura D, Wu RC, Amano M, Iso T, Kedes L, Nishida H, Kaibuchi K, Hamamori Y. Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase. J Biol Chem. 2006 Jun 2;281(22):15320-9. Epub 2006 Mar 30. PMID:16574662 doi:10.1074/jbc.M510954200
↑ Ma Z, Kanai M, Kawamura K, Kaibuchi K, Ye K, Fukasawa K. Interaction between ROCK II and nucleophosmin/B23 in the regulation of centrosome duplication. Mol Cell Biol. 2006 Dec;26(23):9016-34. Epub 2006 Oct 2. PMID:17015463 doi:10.1128/MCB.01383-06
↑ Wang Y, Zheng XR, Riddick N, Bryden M, Baur W, Zhang X, Surks HK. ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res. 2009 Feb 27;104(4):531-40. doi: 10.1161/CIRCRESAHA.108.188524. Epub, 2009 Jan 8. PMID:19131646 doi:10.1161/CIRCRESAHA.108.188524
↑ Lock FE, Hotchin NA. Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte differentiation. PLoS One. 2009 Dec 4;4(12):e8190. doi: 10.1371/journal.pone.0008190. PMID:19997641 doi:10.1371/journal.pone.0008190
↑ Wang HF, Takenaka K, Nakanishi A, Miki Y. BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2. Cancer Res. 2011 Jan 1;71(1):68-77. doi: 10.1158/0008-5472.CAN-10-0030. Epub 2010, Nov 16. PMID:21084279 doi:10.1158/0008-5472.CAN-10-0030
↑ Herskowitz JH, Seyfried NT, Gearing M, Kahn RA, Peng J, Levey AI, Lah JJ. Rho kinase II phosphorylation of the lipoprotein receptor LR11/SORLA alters amyloid-beta production. J Biol Chem. 2011 Feb 25;286(8):6117-27. doi: 10.1074/jbc.M110.167239. Epub 2010 , Dec 8. PMID:21147781 doi:10.1074/jbc.M110.167239
↑ 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. 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. J Med Chem. 2020 Feb 13;63(3):1084-1104. doi: 10.1021/acs.jmedchem.9b01427. Epub , 2020 Jan 14. PMID:31895562 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01427

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6p5m"

Categories: Homo sapiens | Large Structures | Hoffman ID | Skene RJ

@@ Line 3: / Line 3: @@
 <StructureSection load='6p5m' size='340' side='right'caption='[[6p5m]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6p5m]] 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=6P5M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P5M FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6p5m]] 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=6P5M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6P5M FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=O1S:6-(5-methyl-1H-pyrazol-4-yl)-2-[(pyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one'>O1S</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]] 2.65&#8491;</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=O1S:6-(5-methyl-1H-pyrazol-4-yl)-2-[(pyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one'>O1S</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=6p5m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p5m OCA], [https://pdbe.org/6p5m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6p5m RCSB], [https://www.ebi.ac.uk/pdbsum/6p5m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6p5m 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=6p5m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p5m OCA], [http://pdbe.org/6p5m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p5m RCSB], [http://www.ebi.ac.uk/pdbsum/6p5m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p5m 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>
+[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;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 6p5m" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Rho-associated protein kinase|Rho-associated protein kinase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[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]]

6p5m

From Proteopedia

Current revision

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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