2WIH

STRUCTURE OF CDK2-CYCLIN A WITH PHA-848125


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.215 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Identification of N,1,4,4-Tetramethyl-8-{[4-(4-Methylpiperazin-1-Yl)Phenyl]Amino}-4,5-Dihydro-1H-Pyrazolo[4,3-H]Quinazoline-3-Carboxamide (Pha-848125), a Potent, Orally Available Cyclin Dependent Kinase Inhibitor.

Brasca, M.G.Amboldi, N.Ballinari, D.Cameron, A.D.Casale, E.Cervi, G.Colombo, M.Colotta, F.Croci, V.Dalessio, R.Fiorentini, F.Isacchi, A.Mercurio, C.Moretti, W.Panzeri, A.Pastori, W.Pevarello, P.Quartieri, F.Roletto, F.Traquandi, G.Vianello, P.Vulpetti, A.Ciomei, M.

(2009) J Med Chem 52: 5152

  • DOI: https://doi.org/10.1021/jm9006559
  • Primary Citation of Related Structures:  
    2WIH, 2WIP

  • PubMed Abstract: 

    The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.


  • Organizational Affiliation

    Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano (MI), Italy. gabriella.brasca@nervianoms.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CELL DIVISION PROTEIN KINASE 2
A, C
309Homo sapiensMutation(s): 0 
EC: 2.7.1.37
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
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-A2
B, D
265Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P20248 (Homo sapiens)
Explore P20248 
Go to UniProtKB:  P20248
PHAROS:  P20248
GTEx:  ENSG00000145386 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP20248
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
P48
Query on P48

Download Ideal Coordinates CCD File 
E [auth A],
F [auth C]
N,1,4,4-TETRAMETHYL-8-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}-4,5-DIHYDRO-1H-PYRAZOLO[4,3-H]QUINAZOLINE-3-CARBOXAMIDE
C25 H32 N8 O
RXZMYLDMFYNEIM-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
G [auth D]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
P48 Binding MOAD:  2WIH IC50: 45 (nM) from 1 assay(s)
BindingDB:  2WIH IC50: min: 5, max: 590 (nM) from 7 assay(s)
PDBBind:  2WIH IC50: 45 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.215 
  • Space Group: P 62 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 183α = 90
b = 183β = 90
c = 213.56γ = 120
Software Package:
Software NamePurpose
CNXrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2009-07-28
    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: 2019-04-03
    Changes: Data collection, Other, Source and taxonomy