4O2P

Kinase domain of cSrc in complex with a substituted pyrazolopyrimidine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Combining X-ray Crystallography and Molecular Modeling toward the Optimization of Pyrazolo[3,4-d]pyrimidines as Potent c-Src Inhibitors Active in Vivo against Neuroblastoma.

Tintori, C.Fallacara, A.L.Radi, M.Zamperini, C.Dreassi, E.Crespan, E.Maga, G.Schenone, S.Musumeci, F.Brullo, C.Richters, A.Gasparrini, F.Angelucci, A.Festuccia, C.Delle Monache, S.Rauh, D.Botta, M.

(2015) J Med Chem 58: 347-361

  • DOI: https://doi.org/10.1021/jm5013159
  • Primary Citation of Related Structures:  
    4O2P

  • PubMed Abstract: 

    c-Src is a tyrosine kinase belonging to the Src-family kinases. It is overexpressed and/or hyperactivated in a variety of cancer cells, thus its inhibition has been predicted to have therapeutic effects in solid tumors. Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl inhibitor. Herein we describe a multidisciplinary drug discovery approach for the optimization of the lead 3 against c-Src. Starting from the X-ray crystal structure of c-Src in complex with 3, Monte Carlo free energy perturbation calculations were applied to guide the design of c-Src inhibitors with improved activities. As a result, the introduction of a meta hydroxyl group on the C4 anilino ring was computed to be particularly favorable. The potency of the synthesized inhibitors was increased with respect to the starting lead 3. The best identified compounds were also found active in the inhibition of neuroblastoma cell proliferation. Furthermore, compound 29 also showed in vivo activity in xenograft model using SH-SY5Y cells.


  • Organizational Affiliation

    Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena Via Aldo Moro 2, 53100 Siena, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proto-oncogene tyrosine-protein kinase Src
A, B
286Gallus gallusMutation(s): 0 
Gene Names: SRCV-SRC SARCOMA VIRAL ONCOGENE
EC: 2.7.10.2
UniProt
Find proteins for P00523 (Gallus gallus)
Explore P00523 
Go to UniProtKB:  P00523
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00523
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
11V
Query on 11V

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
1-[(2R)-2-chloro-2-phenylethyl]-6-{[2-(morpholin-4-yl)ethyl]sulfanyl}-N-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine
C25 H27 Cl N6 O S
VXPRLPJXOGZRAZ-QFIPXVFZSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
11V Binding MOAD:  4O2P Ki: 200 (nM) from 1 assay(s)
BindingDB:  4O2P Ki: min: 200, max: 240 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.197 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.215α = 101.35
b = 63.248β = 90.44
c = 74.813γ = 90.07
Software Package:
Software NamePurpose
XDSdata scaling
PHASERphasing
REFMACrefinement
XSCALEdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-03-04
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description