2clx

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[[Image:2clx.gif|left|200px]]<br /><applet load="2clx" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2clx.gif|left|200px]]
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caption="2clx, resolution 1.80&Aring;" />
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'''4-ARYLAZO-3,5-DIAMINO-1H-PYRAZOLE CDK INHIBITORS: SAR STUDY, CRYSTAL STRUCTURE IN COMPLEX WITH CDK2, SELECTIVITY, AND CELLULAR EFFECTS'''<br />
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{{Structure
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|PDB= 2clx |SIZE=350|CAPTION= <scene name='initialview01'>2clx</scene>, resolution 1.80&Aring;
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|SITE= <scene name='pdbsite=AC1:F18+Binding+Site+For+Chain+A'>AC1</scene>
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|LIGAND= <scene name='pdbligand=F18:4-[(E)-(3,5-DIAMINO-1H-PYRAZOL-4-YL)DIAZENYL]PHENOL'>F18</scene>
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|ACTIVITY=
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|GENE=
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}}
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'''4-ARYLAZO-3,5-DIAMINO-1H-PYRAZOLE CDK INHIBITORS: SAR STUDY, CRYSTAL STRUCTURE IN COMPLEX WITH CDK2, SELECTIVITY, AND CELLULAR EFFECTS'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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2CLX is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=F18:'>F18</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Known structural/functional Site: <scene name='pdbsite=AC1:F18+Binding+Site+For+Chain+A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CLX OCA].
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2CLX is a [[Single protein]] structure of 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=2CLX OCA].
==Reference==
==Reference==
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4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects., Krystof V, Cankar P, Frysova I, Slouka J, Kontopidis G, Dzubak P, Hajduch M, Srovnal J, de Azevedo WF Jr, Orsag M, Paprskarova M, Rolcik J, Latr A, Fischer PM, Strnad M, J Med Chem. 2006 Nov 2;49(22):6500-9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17064068 17064068]
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4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects., Krystof V, Cankar P, Frysova I, Slouka J, Kontopidis G, Dzubak P, Hajduch M, Srovnal J, de Azevedo WF Jr, Orsag M, Paprskarova M, Rolcik J, Latr A, Fischer PM, Strnad M, J Med Chem. 2006 Nov 2;49(22):6500-9. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17064068 17064068]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: transferase]]
[[Category: transferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:50:07 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:17:04 2008''

Revision as of 14:17, 20 March 2008

Image:2clx.gif


PDB ID 2clx

Drag the structure with the mouse to rotate
, resolution 1.80Å
Sites:
Ligands:
Coordinates: save as pdb, mmCIF, xml



4-ARYLAZO-3,5-DIAMINO-1H-PYRAZOLE CDK INHIBITORS: SAR STUDY, CRYSTAL STRUCTURE IN COMPLEX WITH CDK2, SELECTIVITY, AND CELLULAR EFFECTS


Overview

In a routine screening of our small-molecule compound collection we recently identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study based on 35 analogues suggests ways in which the pharmacophore could be further optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics studies with the lead compound and X-ray crystallography of an inhibitor-CDK2 complex demonstrated that its mode of inhibition is competitive. Functional kinase assays confirmed the selectivity toward CDKs, with a preference for CDK9-cyclin T1. The most potent inhibitor, 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol 31b (CAN508), reduced the frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation assays. Further observed cellular effects included decreased phosphorylation of the retinoblastoma protein and the C-terminal domain of RNA polymerase II, inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53, all of which are consistent with inhibition of CDK9.

About this Structure

2CLX is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects., Krystof V, Cankar P, Frysova I, Slouka J, Kontopidis G, Dzubak P, Hajduch M, Srovnal J, de Azevedo WF Jr, Orsag M, Paprskarova M, Rolcik J, Latr A, Fischer PM, Strnad M, J Med Chem. 2006 Nov 2;49(22):6500-9. PMID:17064068

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