2CLX

4-Arylazo-3,5-diamino-1H-pyrazole CDK Inhibitors: SAR Study, Crystal Structure in Complex with CDK2, Selectivity, and Cellular Effects


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.180 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

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.De Azevedo Junior, W.F.Paprskarova, M.Orsag, M.Rolcik, J.Latr, A.Fischer, P.M.Strnad, M.

(2006) J Med Chem 49: 6500

  • DOI: https://doi.org/10.1021/jm0605740
  • Primary Citation of Related Structures:  
    2CLX

  • PubMed Abstract: 

    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.


  • Organizational Affiliation

    Laboratory of Growth Regulators, Faculty of Science, Palacký University and Institute of Experimental Botany, Slechtitelů 11, 783 71 Olomouc, Czech Republic.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CELL DIVISION PROTEIN KINASE 2298Homo sapiensMutation(s): 0 
EC: 2.7.1.37 (PDB Primary Data), 2.7.11.22 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P24941 (Homo sapiens)
Explore P24941 
Go to UniProtKB:  P24941
PHAROS:  P24941
GTEx:  ENSG00000123374 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24941
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
F18
Query on F18

Download Ideal Coordinates CCD File 
B [auth A]4-[(E)-(3,5-DIAMINO-1H-PYRAZOL-4-YL)DIAZENYL]PHENOL
C9 H10 N6 O
AYZRKFOEZQBUEA-SEYXRHQNSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
F18 BindingDB:  2CLX Ki: 6.90e+4 (nM) from 1 assay(s)
IC50: min: 2.00e+4, max: 6.90e+4 (nM) from 2 assay(s)
PDBBind:  2CLX Ki: 1.33e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.180 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.37α = 90
b = 70.75β = 90
c = 72.18γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
d*TREKdata reduction
d*TREKdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2006-11-01
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-01-30
    Changes: Data collection, Experimental preparation, Other
  • Version 1.4: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description