3BZ3

Crystal Structure Analysis of Focal Adhesion Kinase with a Methanesulfonamide Diaminopyrimidine Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.160 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271.

Roberts, W.G.Ung, E.Whalen, P.Cooper, B.Hulford, C.Autry, C.Richter, D.Emerson, E.Lin, J.Kath, J.Coleman, K.Yao, L.Martinez-Alsina, L.Lorenzen, M.Berliner, M.Luzzio, M.Patel, N.Schmitt, E.LaGreca, S.Jani, J.Wessel, M.Marr, E.Griffor, M.Vajdos, F.

(2008) Cancer Res 68: 1935-1944

  • DOI: https://doi.org/10.1158/0008-5472.CAN-07-5155
  • Primary Citation of Related Structures:  
    3BZ3

  • PubMed Abstract: 

    Cancer cells are characterized by the ability to grow in an anchorage-independent manner. The activity of the nonreceptor tyrosine kinase, focal adhesion kinase (FAK), is thought to contribute to this phenotype. FAK localizes in focal adhesion plaques and has a role as a scaffolding and signaling protein for other adhesion molecules. Recent studies show a strong correlation between increased FAK expression and phosphorylation status and the invasive phenotype of aggressive human tumors. PF-562,271 is a potent, ATP-competitive, reversible inhibitor of FAK and Pyk2 catalytic activity with a IC(50) of 1.5 and 14 nmol/L, respectively. Additionally, PF-562,271 displayed robust inhibition in an inducible cell-based assay measuring phospho-FAK with an IC(50) of 5 nmol/L. PF-562,271 was evaluated against multiple kinases and displays >100x selectivity against a long list of nontarget kinases. PF-562,271 inhibits FAK phosphorylation in vivo in a dose-dependent fashion (calculated EC(50) of 93 ng/mL, total) after p.o. administration to tumor-bearing mice. In vivo inhibition of FAK phosphorylation (>50%) was sustained for >4 hours with a single p.o. dose of 33 mg/kg. Antitumor efficacy and regressions were observed in multiple human s.c. xenograft models. No weight loss, morbidity, or mortality were observed in any in vivo experiment. Tumor growth inhibition was dose and drug exposure dependent. Taken together, these data show that kinase inhibition with an ATP-competitive small molecule inhibitor of FAK decreases the phospho-status in vivo, resulting in robust antitumor activity.


  • Organizational Affiliation

    Pfizer Oncology, Groton, Connecticut, USA. robertswg@oncoviarx.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Focal adhesion kinase 1276Homo sapiensMutation(s): 0 
Gene Names: PTK2FAKFAK1
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q05397 (Homo sapiens)
Explore Q05397 
Go to UniProtKB:  Q05397
PHAROS:  Q05397
GTEx:  ENSG00000169398 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ05397
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
YAM
Query on YAM

Download Ideal Coordinates CCD File 
B [auth A]N-methyl-N-{3-[({2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}methanesulfonamide
C21 H20 F3 N7 O3 S
MZDKLVOWGIOKTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
YAM BindingDB:  3BZ3 IC50: min: 1, max: 1.5 (nM) from 2 assay(s)
PDBBind:  3BZ3 IC50: 1.5 (nM) from 1 assay(s)
Binding MOAD:  3BZ3 IC50: 1.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.156 
  • R-Value Observed: 0.160 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.46α = 90
b = 47.825β = 98.43
c = 63.067γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-04-01
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Refinement description