3ET7

Crystal structure of PYK2 complexed with PF-2318841


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.328 
  • R-Value Work: 0.247 
  • R-Value Observed: 0.251 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation.

Walker, D.P.Bi, F.C.Kalgutkar, A.S.Bauman, J.N.Zhao, S.X.Soglia, J.R.Aspnes, G.E.Kung, D.W.Klug-McLeod, J.Zawistoski, M.P.McGlynn, M.A.Oliver, R.Dunn, M.Li, J.C.Richter, D.T.Cooper, B.A.Kath, J.C.Hulford, C.A.Autry, C.L.Luzzio, M.J.Ung, E.J.Roberts, W.G.Bonnette, P.C.Buckbinder, L.Mistry, A.Griffor, M.C.Han, S.Guzman-Perez, A.

(2008) Bioorg Med Chem Lett 18: 6071-6077

  • DOI: https://doi.org/10.1016/j.bmcl.2008.10.030
  • Primary Citation of Related Structures:  
    3ET7

  • PubMed Abstract: 

    The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.


  • Organizational Affiliation

    Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. daniel.p.walker@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein tyrosine kinase 2 beta277Homo sapiensMutation(s): 0 
Gene Names: PTK2BFAK2PYK2RAFTK
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q14289 (Homo sapiens)
Explore Q14289 
Go to UniProtKB:  Q14289
PHAROS:  Q14289
GTEx:  ENSG00000120899 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ14289
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
349
Query on 349

Download Ideal Coordinates CCD File 
B [auth A]5-{[4-{[2-(pyrrolidin-1-ylsulfonyl)benzyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-1,3-dihydro-2H-indol-2-one
C24 H21 F3 N6 O3 S
TWFBJYGVNVQOCW-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
C [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Binding Affinity Annotations 
IDSourceBinding Affinity
349 PDBBind:  3ET7 IC50: 17 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.328 
  • R-Value Work: 0.247 
  • R-Value Observed: 0.251 
  • Space Group: P 4 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 106.824α = 90
b = 106.824β = 90
c = 75.185γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-06-23 
  • Deposition Author(s): Han, S.

Revision History  (Full details and data files)

  • Version 1.0: 2009-06-23
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-12-27
    Changes: Data collection, Database references, Derived calculations