2WPA

Optimisation of 6,6-Dimethyl Pyrrolo 3,4-c pyrazoles: Identification of PHA-793887, a Potent CDK Inhibitor Suitable for Intravenous Dosing


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.51 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Optimization of 6,6-Dimethyl Pyrrolo[3,4-C]Pyrazoles: Identification of Pha-793887, a Potent Cdk Inhibitor Suitable for Intravenous Dosing.

Brasca, M.G.Albanese, C.Alzani, R.Amici, R.Avanzi, N.Ballinari, D.Bischoff, J.Borghi, D.Casale, E.Croci, V.Fiorentini, F.Isacchi, A.Mercurio, C.Nesi, M.Orsini, P.Pastori, W.Pesenti, E.Pevarello, P.Roussel, P.Varasi, M.Volpi, D.Vulpetti, A.Ciomei, M.

(2010) Bioorg Med Chem 18: 1844

  • DOI: https://doi.org/10.1016/j.bmc.2010.01.042
  • Primary Citation of Related Structures:  
    2WPA

  • PubMed Abstract: 

    We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors.


  • Organizational Affiliation

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


Macromolecules
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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
Binding Affinity Annotations 
IDSourceBinding Affinity
889 PDBBind:  2WPA IC50: 8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.51 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 
  • Space Group: P 62 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 186.533α = 90
b = 186.533β = 90
c = 215.133γ = 120
Software Package:
Software NamePurpose
CNXrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2010-02-23
    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