2wpa: Difference between revisions

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[[Image:~~2wpa~~.~~png~~|~~left~~|~~200px~~]]

==OPTIMISATION OF 6,6-DIMETHYL PYRROLO 3,4-C PYRAZOLES: IDENTIFICATION OF PHA-793887, A POTENT CDK INHIBITOR SUITABLE FOR INTRAVENOUS DOSING==

== Structural highlights ==

<table><tr><td colspan='2'>[[2wpa]] is a 4 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=2WPA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WPA FirstGlance]. <br>

</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=889:N-{6,6-DIMETHYL-5-[(1-METHYLPIPERIDIN-4-YL)CARBONYL]-1,4,5,6-TETRAHYDROPYRROLO[3,4-C]PYRAZOL-3-YL}-3-METHYLBUTANAMIDE'>889</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br>

<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wpa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wpa OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wpa RCSB], [http://www.ebi.ac.uk/pdbsum/2wpa PDBsum]</span></td></tr>

<table>

== Evolutionary Conservation ==

[[Image:Consurf_key_small.gif|200px|right]]

Check<jmol>

<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wp/2wpa_consurf.spt"</scriptWhenChecked>

<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>

<text>to colour the structure by Evolutionary Conservation</text>

</jmolCheckbox>

</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].

== Publication Abstract from PubMed ==

We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors.

~~{{STRUCTURE_2wpa| PDB=2wpa | SCENE= }}~~

Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing.,Brasca MG, Albanese C, Alzani R, Amici R, Avanzi N, Ballinari D, Bischoff J, Borghi D, Casale E, Croci V, Fiorentini F, Isacchi A, Mercurio C, Nesi M, Orsini P, Pastori W, Pesenti E, Pevarello P, Roussel P, Varasi M, Volpi D, Vulpetti A, Ciomei M Bioorg Med Chem. 2010 Mar 1;18(5):1844-53. Epub 2010 Jan 25. PMID:20153204<ref>PMID:20153204</ref>

~~===OPTIMISATION OF 6~~,~~6-DIMETHYL PYRROLO 3,4-C PYRAZOLES: IDENTIFICATION OF PHA-793887, A POTENT CDK INHIBITOR SUITABLE FOR INTRAVENOUS DOSING===~~

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

</div>

~~{{ABSTRACT_PUBMED_20153204}}~~

~~==About this Structure==~~

~~[[2wpa]] is~~ a ~~4 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=2WPA OCA].~~

==See Also==

*[[Cell ~~Division Protein Kinase~~ 2|Cell ~~Division Protein Kinase~~ 2]]

*[[Cell division protein kinase 2|Cell division protein kinase 2]]

*[[Cyclin|Cyclin]]

== References ==

==~~Reference~~==

<~~ref group="xtra">PMID:020153204<~~/~~ref~~><~~references group="xtra"~~/>

__TOC__

</StructureSection>

[[Category: Homo sapiens]]

[[Category: Non-specific serine/threonine protein kinase]]

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-[[Image:2wpa.png|left|200px]]
+==OPTIMISATION OF 6,6-DIMETHYL PYRROLO 3,4-C PYRAZOLES: IDENTIFICATION OF PHA-793887, A POTENT CDK INHIBITOR SUITABLE FOR INTRAVENOUS DOSING==
+<StructureSection load='2wpa' size='340' side='right' caption='[[2wpa]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2wpa]] is a 4 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=2WPA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WPA FirstGlance]. <br>
+</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=889:N-{6,6-DIMETHYL-5-[(1-METHYLPIPERIDIN-4-YL)CARBONYL]-1,4,5,6-TETRAHYDROPYRROLO[3,4-C]PYRAZOL-3-YL}-3-METHYLBUTANAMIDE'>889</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br>
+<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1pye|1pye]], [[1h08|1h08]], [[2vth|2vth]], [[2b53|2b53]], [[1v1k|1v1k]], [[1okv|1okv]], [[1h25|1h25]], [[1ke7|1ke7]], [[1pxk|1pxk]], [[2wih|2wih]], [[2bhh|2bhh]], [[2vta|2vta]], [[2uue|2uue]], [[1gz8|1gz8]], [[1e1v|1e1v]], [[1ol2|1ol2]], [[1h27|1h27]], [[1jsv|1jsv]], [[2b52|2b52]], [[2wha|2wha]], [[1ke5|1ke5]], [[1fin|1fin]], [[2c5o|2c5o]], [[2c68|2c68]], [[2vtt|2vtt]], [[1p2a|1p2a]], [[2c4g|2c4g]], [[2vtq|2vtq]], [[1h1q|1h1q]], [[1w0x|1w0x]], [[1pxo|1pxo]], [[2w05|2w05]], [[1ke9|1ke9]], [[2a0c|2a0c]], [[1hck|1hck]], [[1jsu|1jsu]], [[1pxn|1pxn]], [[2uze|2uze]], [[2v0d|2v0d]], [[2vtm|2vtm]], [[1oiq|1oiq]], [[1h1r|1h1r]], [[2iw8|2iw8]], [[1pw2|1pw2]], [[1hcl|1hcl]], [[1gih|1gih]], [[2whb|2whb]], [[2w06|2w06]], [[2vtn|2vtn]], [[1jst|1jst]], [[1oiu|1oiu]], [[1pxm|1pxm]], [[1b38|1b38]], [[1fq1|1fq1]], [[1vyw|1vyw]], [[1h1p|1h1p]], [[2wma|2wma]], [[2c69|2c69]], [[1urc|1urc]], [[1pxi|1pxi]], [[2c6i|2c6i]], [[1ykr|1ykr]], [[2w17|2w17]], [[2c6k|2c6k]], [[2c5y|2c5y]], [[2uzd|2uzd]], [[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]], [[2g9x|2g9x]], [[2bkz|2bkz]], [[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]], [[2vu3|2vu3]], [[2b55|2b55]], [[1ogu|1ogu]], [[1pf8|1pf8]], [[1h1s|1h1s]], [[2c5v|2c5v]], [[2jgz|2jgz]], [[2bhe|2bhe]], [[1urw|1urw]], [[1oiy|1oiy]], [[2c6l|2c6l]], [[1f5q|1f5q]], [[2c6o|2c6o]], [[2vtl|2vtl]], [[1ol1|1ol1]], [[1h01|1h01]], [[2uzb|2uzb]], [[2wfy|2wfy]], [[1oir|1oir]], [[1oi9|1oi9]], [[2vtj|2vtj]], [[2cjm|2cjm]], [[2c5n|2c5n]], [[2wev|2wev]], [[2c5x|2c5x]], [[2c6m|2c6m]], [[1oit|1oit]], [[1gy3|1gy3]], [[2v22|2v22]], [[2vv9|2vv9]], [[1di8|1di8]], [[1gii|1gii]], [[2wmb|2wmb]], [[1e9h|1e9h]], [[1dm2|1dm2]], [[2vto|2vto]], [[1h24|1h24]], [[2uzo|2uzo]], [[2exm|2exm]], [[1h00|1h00]], [[2clx|2clx]], [[1pxp|1pxp]], [[2cch|2cch]], [[2btr|2btr]], [[1b39|1b39]], [[1aq1|1aq1]], [[1h0w|1h0w]], [[1g5s|1g5s]], [[1ckp|1ckp]], [[1pxl|1pxl]], [[1h28|1h28]], [[1ke8|1ke8]], [[2vtr|2vtr]], [[1h26|1h26]], [[1h07|1h07]], [[1e1x|1e1x]], [[1y8y|1y8y]]</td></tr>
+<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wpa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wpa OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wpa RCSB], [http://www.ebi.ac.uk/pdbsum/2wpa PDBsum]</span></td></tr>
+<table>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wp/2wpa_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors.
-{{STRUCTURE_2wpa|  PDB=2wpa  |  SCENE=  }}
+Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing.,Brasca MG, Albanese C, Alzani R, Amici R, Avanzi N, Ballinari D, Bischoff J, Borghi D, Casale E, Croci V, Fiorentini F, Isacchi A, Mercurio C, Nesi M, Orsini P, Pastori W, Pesenti E, Pevarello P, Roussel P, Varasi M, Volpi D, Vulpetti A, Ciomei M Bioorg Med Chem. 2010 Mar 1;18(5):1844-53. Epub 2010 Jan 25. PMID:20153204<ref>PMID:20153204</ref>
-===OPTIMISATION OF 6,6-DIMETHYL PYRROLO 3,4-C PYRAZOLES: IDENTIFICATION OF PHA-793887, A POTENT CDK INHIBITOR SUITABLE FOR INTRAVENOUS DOSING===
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-{{ABSTRACT_PUBMED_20153204}}
-==About this Structure==
-[[2wpa]] is a 4 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=2WPA OCA].
 ==See Also==
-*[[Cell Division Protein Kinase 2|Cell Division Protein Kinase 2]]
+*[[Cell division protein kinase 2|Cell division protein kinase 2]]
 *[[Cyclin|Cyclin]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:020153204</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
 [[Category: Non-specific serine/threonine protein kinase]]