3KRJ

cFMS tyrosine kinase in complex with 4-Cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.213 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Optimization of a Potent Class of Arylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading to Anti-inflammatory Clinical Candidate 4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide (JNJ-28312141).

Illig, C.R.Manthey, C.L.Wall, M.J.Meegalla, S.K.Chen, J.Wilson, K.J.Ballentine, S.K.Desjarlais, R.L.Schubert, C.Crysler, C.S.Chen, Y.Molloy, C.J.Chaikin, M.A.Donatelli, R.R.Yurkow, E.Zhou, Z.Player, M.R.Tomczuk, B.E.

(2011) J Med Chem 54: 7860-7883

  • DOI: https://doi.org/10.1021/jm200900q
  • Primary Citation of Related Structures:  
    3KRJ, 3KRL

  • PubMed Abstract: 

    A class of potent inhibitors of colony-stimulating factor-1 receptor (CSF-1R or FMS), as exemplified by 8 and 21, was optimized to improve pharmacokinetic and pharmacodynamic properties and potential toxicological liabilities. Early stage absorption, distribution, metabolism, and excretion assays were employed to ensure the incorporation of druglike properties resulting in the selection of several compounds with good activity in a pharmacodynamic screening assay in mice. Further investigation, utilizing the type II collagen-induced arthritis model in mice, culminated in the selection of anti-inflammatory development candidate JNJ-28312141 (23, FMS IC(50) = 0.69 nM, cell assay IC(50) = 2.6 nM). Compound 23 also demonstrated efficacy in rat adjuvant and streptococcal cell wall-induced models of arthritis and has entered phase I clinical trials.


  • Organizational Affiliation

    Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, Pennsylvania 19477, United States. cillig@its.jnj.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Macrophage colony-stimulating factor 1 receptor, Basic fibroblast growth factor receptor 1335Homo sapiensMutation(s): 1 
Gene Names: CSF1RFMSFGFR1
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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
KRJ
Query on KRJ

Download Ideal Coordinates CCD File 
C [auth A]4-cyano-N-(2-cyclohex-1-en-1-yl-4-piperidin-4-ylphenyl)-1H-imidazole-2-carboxamide
C22 H25 N5 O
XPCQXAQALLRVJQ-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
B [auth A]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
KRJ PDBBind:  3KRJ IC50: 1.1 (nM) from 1 assay(s)
Binding MOAD:  3KRJ IC50: 1.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.213 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.875α = 90
b = 82.875β = 90
c = 144.408γ = 120
Software Package:
Software NamePurpose
PHENIXmodel building
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2010-12-01 
  • Deposition Author(s): Schubert, C.

Revision History  (Full details and data files)

  • Version 1.0: 2010-12-01
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2011-12-14
    Changes: Database references
  • Version 1.3: 2017-08-23
    Changes: Source and taxonomy
  • Version 1.4: 2021-10-13
    Changes: Database references, Derived calculations
  • Version 1.5: 2023-09-06
    Changes: Data collection, Refinement description