3DPK

cFMS tyrosine kinase in complex with a pyridopyrimidinone inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.192 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors

Huang, H.Hutta, D.A.Rinker, J.M.Hu, H.Parsons, W.H.Schubert, C.DesJarlais, R.L.Crysler, C.S.Chaikin, M.A.Donatelli, R.R.Chen, Y.Cheng, D.Zhou, Z.Yurkow, E.Manthey, C.L.Player, M.R.

(2009) J Med Chem 52: 1081-1099

  • DOI: https://doi.org/10.1021/jm801406h
  • Primary Citation of Related Structures:  
    3DPK

  • PubMed Abstract: 

    A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.


  • Organizational Affiliation

    Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, Pennsylvania 19477-0776, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Macrophage colony-stimulating factor 1 receptor, Fibroblast growth factor receptor 1335Homo sapiensMutation(s): 0 
Gene Names: CSF1RFGFBRFGFR1FLGFLT2FMSBFGFRCEKHBGFR
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P11362 (Homo sapiens)
Explore P11362 
Go to UniProtKB:  P11362
PHAROS:  P11362
GTEx:  ENSG00000077782 
Find proteins for P07333 (Homo sapiens)
Explore P07333 
Go to UniProtKB:  P07333
PHAROS:  P07333
GTEx:  ENSG00000182578 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP11362P07333
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
8C5 PDBBind:  3DPK IC50: 4.1 (nM) from 1 assay(s)
Binding MOAD:  3DPK IC50: 4.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.192 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 80.95α = 90
b = 80.95β = 90
c = 145.42γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
CNXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-02-17 
  • Deposition Author(s): Schubert, C.

Revision History  (Full details and data files)

  • Version 1.0: 2009-02-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-01-25
    Changes: Database references, Source and taxonomy
  • Version 1.3: 2017-07-26
    Changes: Source and taxonomy
  • Version 1.4: 2017-10-25
    Changes: Refinement description
  • Version 1.5: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description