2OFU

x-ray crystal structure of 2-aminopyrimidine carbamate 43 bound to Lck


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.291 
  • R-Value Work: 0.228 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Novel 2-Aminopyrimidine Carbamates as Potent and Orally Active Inhibitors of Lck: Synthesis, SAR, and in Vivo Antiinflammatory Activity

Martin, M.W.Newcomb, J.Nunes, J.J.McGowan, D.C.Armistead, D.M.Boucher, C.Buchanan, J.L.Buckner, W.Chai, L.Elbaum, D.Epstein, L.F.Faust, T.Flynn, S.Gallant, P.Gore, A.Gu, Y.Hsieh, F.Huang, X.Lee, J.H.Metz, D.Middleton, S.Mohn, D.Morgenstern, K.Morrison, M.J.Novak, P.M.Oliveira-dos-Santos, A.Powers, D.Rose, P.Schneider, S.Sell, S.Tudor, Y.Turci, S.M.Welcher, A.A.White, R.D.Zack, D.Zhao, H.Zhu, L.Zhu, X.Ghiron, C.Amouzegh, P.Ermann, M.Jenkins, J.Johnston, D.Napier, S.Power, E.

(2006) J Med Chem 49: 4981

  • DOI: https://doi.org/10.1021/jm060435i
  • Primary Citation of Related Structures:  
    2OFU

  • PubMed Abstract: 

    The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.


  • Organizational Affiliation

    Department of Chemistry Research and Discovery, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, USA. matmarti@amgen.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proto-oncogene tyrosine-protein kinase LCK273Homo sapiensMutation(s): 1 
Gene Names: LCK
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P06239 (Homo sapiens)
Explore P06239 
Go to UniProtKB:  P06239
PHAROS:  P06239
GTEx:  ENSG00000182866 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06239
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1N9
Query on 1N9

Download Ideal Coordinates CCD File 
C [auth A]2,6-DIMETHYLPHENYL 2-(3,5-DIMETHOXY-4-(3-(4-METHYLPIPERAZIN-1-YL)PROPOXY)PHENYLAMINO)PYRIMIDIN- 4-YL(2,4-DIMETHOXYPHENYL)CARBAMATE
C37 H46 N6 O7
VSJXTUFWPAOYLC-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
PTR BindingDB:  2OFU Kd: 4.00e+5 (nM) from 1 assay(s)
1N9 PDBBind:  2OFU IC50: 1 (nM) from 1 assay(s)
BindingDB:  2OFU IC50: 0.6 (nM) from 1 assay(s)
Binding MOAD:  2OFU IC50: 0.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.291 
  • R-Value Work: 0.228 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.43α = 90
b = 73.53β = 90
c = 92.81γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2007-02-27 
  • Deposition Author(s): Huang, X.

Revision History  (Full details and data files)

  • Version 1.0: 2007-02-27
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.4: 2023-11-15
    Changes: Data collection