2clx: Difference between revisions
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==Overview== | ==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 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== | ==About this Structure== | ||
2CLX is a | 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 F18 as [http://en.wikipedia.org/wiki/ligand ligand]. Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CLX OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 13:51:56 2007'' | ||
Revision as of 14:46, 5 November 2007
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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
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 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 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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OCA- Pages with broken file links
- Homo sapiens
- Single protein
- Cankar, P.
- Deazevedo, W.F.
- Dzubak, P.
- Fischer, P.M.
- Frysova, I.
- Hajduch, M.
- Kontopidis, G.
- Krystof, V.
- Latr, A.
- Orsag, M.
- Paprskarova, M.
- Rolcik, J.
- Slouka, J.
- Strnad, M.
- F18
- Atp-binding
- Cdk2
- Cell cycle
- Cell division
- Kinase
- Mitosis
- Nucleotide-binding
- Phosphorylation
- Polymorphism
- Serine-threonine-protein kinase
- Serine/threonine- protein kinase
- Transferase