2clx: Difference between revisions

Revision as of 17:50, 21 February 2008

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 as ligand. Known structural/functional Site: . 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

Page seeded by OCA on Thu Feb 21 16:50:07 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 4: / Line 4: @@
 ==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.
+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==
@@ Line 14: / Line 14: @@
 [[Category: Single protein]]
 [[Category: Cankar, P.]]
-[[Category: Deazevedo, W.F.]]
+[[Category: Deazevedo, W F.]]
 [[Category: Dzubak, P.]]
-[[Category: Fischer, P.M.]]
+[[Category: Fischer, P M.]]
 [[Category: Frysova, I.]]
 [[Category: Hajduch, M.]]
@@ Line 41: / Line 41: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 10:36:46 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:50:07 2008''