2clx

File:2clx.gif

spinqualitylabelsall models 2clx, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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

OverviewOverview

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 ... [(full description)]

About this StructureAbout this Structure

2CLX is a [Single protein] structure of sequence from [Homo sapiens] with F18 as [ligand]. Structure known Active Site: AC1. Full crystallographic information is available from [OCA].

ReferenceReference

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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