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[[ | ==Discovery and Characterisation of 2-Anilino-4-(thiazol-5-yl) pyrimidine Transcriptional CDK Inhibitors as Anticancer Agents== | ||
<StructureSection load='2xnb' size='340' side='right' caption='[[2xnb]], [[Resolution|resolution]] 1.85Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2xnb]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XNB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XNB FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Y8L:3,4-DIMETHYL-5-(2-{[(1Z)-4-PIPERAZIN-1-YLCYCLOHEXA-2,4-DIEN-1-YLIDENE]AMINO}PYRIMIDIN-4-YL)-1,3-THIAZOL-2(3H)-ONE'>Y8L</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1pye|1pye]], [[1h08|1h08]], [[2vth|2vth]], [[2b53|2b53]], [[1v1k|1v1k]], [[1ke7|1ke7]], [[1okv|1okv]], [[1h25|1h25]], [[1pxk|1pxk]], [[2wih|2wih]], [[2bhh|2bhh]], [[2vta|2vta]], [[2uue|2uue]], [[1gz8|1gz8]], [[1e1v|1e1v]], [[1ol2|1ol2]], [[1h27|1h27]], [[1jsv|1jsv]], [[2b52|2b52]], [[1ke5|1ke5]], [[1fin|1fin]], [[2c5o|2c5o]], [[2c68|2c68]], [[2x1n|2x1n]], [[2vtt|2vtt]], [[1p2a|1p2a]], [[2vtq|2vtq]], [[2c4g|2c4g]], [[1h1q|1h1q]], [[1w0x|1w0x]], [[2w05|2w05]], [[1pxo|1pxo]], [[1ke9|1ke9]], [[2a0c|2a0c]], [[1hck|1hck]], [[1jsu|1jsu]], [[1pxn|1pxn]], [[2uze|2uze]], [[2v0d|2v0d]], [[2vtm|2vtm]], [[1oiq|1oiq]], [[1h1r|1h1r]], [[2iw8|2iw8]], [[1gih|1gih]], [[1hcl|1hcl]], [[1pw2|1pw2]], [[2whb|2whb]], [[2vtn|2vtn]], [[2w06|2w06]], [[1jst|1jst]], [[1oiu|1oiu]], [[1b38|1b38]], [[1pxm|1pxm]], [[1fq1|1fq1]], [[1vyw|1vyw]], [[1h1p|1h1p]], [[2wma|2wma]], [[2c69|2c69]], [[1urc|1urc]], [[1pxi|1pxi]], [[2c6i|2c6i]], [[2wxv|2wxv]], [[1ykr|1ykr]], [[2w17|2w17]], [[2uzd|2uzd]], [[2c6k|2c6k]], [[2c5y|2c5y]], [[1wcc|1wcc]], [[2j9m|2j9m]], [[1vyz|1vyz]], [[2vti|2vti]], [[1jvp|1jvp]], [[1w98|1w98]], [[2wip|2wip]], [[1pkd|1pkd]], [[1p5e|1p5e]], [[2vts|2vts]], [[2c5p|2c5p]], [[2uzn|2uzn]], [[2b54|2b54]], [[1ke6|1ke6]], [[1pxj|1pxj]], [[2uzl|2uzl]], [[2cci|2cci]], [[2bkz|2bkz]], [[2g9x|2g9x]], [[1y91|1y91]], [[2iw6|2iw6]], [[1gij|1gij]], [[1r78|1r78]], [[1h0v|1h0v]], [[2iw9|2iw9]], [[1w8c|1w8c]], [[1buh|1buh]], [[2bpm|2bpm]], [[2bts|2bts]], [[1fvv|1fvv]], [[1okw|1okw]], [[2a4l|2a4l]], [[2vtp|2vtp]], [[2c6t|2c6t]], [[1fvt|1fvt]], [[1qmz|1qmz]], [[2w1h|2w1h]], [[2xmy|2xmy]], [[2vu3|2vu3]], [[1ogu|1ogu]], [[2b55|2b55]], [[1pf8|1pf8]], [[1h1s|1h1s]], [[2jgz|2jgz]], [[2c5v|2c5v]], [[2bhe|2bhe]], [[1urw|1urw]], [[1oiy|1oiy]], [[2c6l|2c6l]], [[1f5q|1f5q]], [[2c6o|2c6o]], [[2vtl|2vtl]], [[1ol1|1ol1]], [[1h01|1h01]], [[2wfy|2wfy]], [[2uzb|2uzb]], [[1oir|1oir]], [[1oi9|1oi9]], [[2vtj|2vtj]], [[2cjm|2cjm]], [[2c5n|2c5n]], [[2c5x|2c5x]], [[2wev|2wev]], [[2c6m|2c6m]], [[1oit|1oit]], [[2v22|2v22]], [[1gy3|1gy3]], [[2vv9|2vv9]], [[1gii|1gii]], [[1di8|1di8]], [[2wpa|2wpa]], [[1e9h|1e9h]], [[2wmb|2wmb]], [[1dm2|1dm2]], [[2vto|2vto]], [[1h24|1h24]], [[2uzo|2uzo]], [[2exm|2exm]], [[1h00|1h00]], [[2clx|2clx]], [[1pxp|1pxp]], [[2cch|2cch]], [[1b39|1b39]], [[2btr|2btr]], [[1aq1|1aq1]], [[1h0w|1h0w]], [[1g5s|1g5s]], [[1ckp|1ckp]], [[1h28|1h28]], [[1pxl|1pxl]], [[1ke8|1ke8]], [[1h26|1h26]], [[2vtr|2vtr]], [[1e1x|1e1x]], [[1h07|1h07]], [[1y8y|1y8y]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin-dependent kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.22 2.7.11.22] </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=2xnb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xnb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2xnb RCSB], [http://www.ebi.ac.uk/pdbsum/2xnb PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The main difficulty in the development of ATP antagonist kinase inhibitors is target specificity, since the ATP-binding motif is present in many proteins. We introduce a strategy that has allowed us to identify compounds from a kinase inhibitor library that block the cyclin-dependent kinases responsible for regulating transcription, i.e., CDK7 and especially CDK9. The screening cascade employs cellular phenotypic assays based on mitotic index and nuclear p53 protein accumulation. This permitted us to classify compounds into transcriptional, cell cycle, and mitotic inhibitor groups. We describe the characterization of the transcriptional inhibitor class in terms of kinase inhibition profile, cellular mode of action, and selectivity for transformed cells. A structural selectivity rationale was used to optimize potency and biopharmaceutical properties and led to the development of a transcriptional inhibitor, 3,4-dimethyl-5-[2-(4-piperazin-1-yl-phenylamino)-pyrimidin-4-yl]-3H-thiazol-2-one , with anticancer activity in animal models. | |||
Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents.,Wang S, Griffiths G, Midgley CA, Barnett AL, Cooper M, Grabarek J, Ingram L, Jackson W, Kontopidis G, McClue SJ, McInnes C, McLachlan J, Meades C, Mezna M, Stuart I, Thomas MP, Zheleva DI, Lane DP, Jackson RC, Glover DM, Blake DG, Fischer PM Chem Biol. 2010 Oct 29;17(10):1111-21. PMID:21035734<ref>PMID:21035734</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Cell | *[[Cell division protein kinase 2|Cell division protein kinase 2]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Cyclin-dependent kinase]] | [[Category: Cyclin-dependent kinase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
Revision as of 15:54, 22 October 2014
Discovery and Characterisation of 2-Anilino-4-(thiazol-5-yl) pyrimidine Transcriptional CDK Inhibitors as Anticancer AgentsDiscovery and Characterisation of 2-Anilino-4-(thiazol-5-yl) pyrimidine Transcriptional CDK Inhibitors as Anticancer Agents
Structural highlightsPublication Abstract from PubMedThe main difficulty in the development of ATP antagonist kinase inhibitors is target specificity, since the ATP-binding motif is present in many proteins. We introduce a strategy that has allowed us to identify compounds from a kinase inhibitor library that block the cyclin-dependent kinases responsible for regulating transcription, i.e., CDK7 and especially CDK9. The screening cascade employs cellular phenotypic assays based on mitotic index and nuclear p53 protein accumulation. This permitted us to classify compounds into transcriptional, cell cycle, and mitotic inhibitor groups. We describe the characterization of the transcriptional inhibitor class in terms of kinase inhibition profile, cellular mode of action, and selectivity for transformed cells. A structural selectivity rationale was used to optimize potency and biopharmaceutical properties and led to the development of a transcriptional inhibitor, 3,4-dimethyl-5-[2-(4-piperazin-1-yl-phenylamino)-pyrimidin-4-yl]-3H-thiazol-2-one , with anticancer activity in animal models. Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents.,Wang S, Griffiths G, Midgley CA, Barnett AL, Cooper M, Grabarek J, Ingram L, Jackson W, Kontopidis G, McClue SJ, McInnes C, McLachlan J, Meades C, Mezna M, Stuart I, Thomas MP, Zheleva DI, Lane DP, Jackson RC, Glover DM, Blake DG, Fischer PM Chem Biol. 2010 Oct 29;17(10):1111-21. PMID:21035734[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCACategories:
- Cyclin-dependent kinase
- Homo sapiens
- Barnett, A L.
- Blake, D G.
- Cooper, M.
- Fischer, P M.
- Glover, D M.
- Grabarek, J.
- Griffiths, G.
- Ingram, L.
- Jackson, R C.
- Jackson, W.
- Kontopidis, G.
- Lane, D P.
- Mcclue, S J.
- Mcinnes, C.
- Mclachlan, J.
- Meades, C.
- Mezna, M.
- Midgley, C A.
- Stuart, I.
- Thomas, M P.
- Wang, S.
- Zheleva, D I.
- Cdk9 inhibitor
- Cell cycle
- Transferase