2OFV

crystal structure of aminoquinazoline 1 bound to Lck


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.301 
  • R-Value Work: 0.274 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Discovery of Aminoquinazolines as Potent, Orally Bioavailable Inhibitors of Lck: Synthesis, SAR, and in Vivo Anti-Inflammatory Activity

DiMauro, E.F.Newcomb, J.Nunes, J.J.Bemis, J.E.Boucher, C.Buchanan, J.L.Buckner, W.H.Cee, V.J.Chai, L.Deak, H.L.Epstein, L.F.Faust, T.Gallant, P.Geuns-Meyer, S.D.Gore, A.Gu, Y.Henkle, B.Hodous, B.L.Hsieh, F.Huang, X.Kim, J.L.Lee, J.H.Martin, M.W.Masse, C.E.McGowan, D.C.Metz, D.Mohn, D.Morgenstern, K.A.Oliveira-dos-Santos, A.Patel, V.F.Powers, D.Rose, P.E.Schneider, S.Tomlinson, S.A.Tudor, Y.-Y.Turci, S.M.Welcher, A.A.White, R.D.Zhao, H.Zhu, L.Zhu, X.

(2006) J Med Chem 49: 5671

  • DOI: https://doi.org/10.1021/jm0605482
  • Primary Citation of Related Structures:  
    2OFV, 2OG8

  • PubMed Abstract: 

    The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (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. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts 02139, USA. edimauro@amgen.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proto-oncogene tyrosine-protein kinase LCK
A, B
277Homo sapiensMutation(s): 0 
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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
242
Query on 242

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
3-(2-AMINOQUINAZOLIN-6-YL)-4-METHYL-N-[3-(TRIFLUOROMETHYL)PHENYL]BENZAMIDE
C23 H17 F3 N4 O
YEIASMOUYNOXGA-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
242 PDBBind:  2OFV IC50: 0.2 (nM) from 1 assay(s)
BindingDB:  2OFV IC50: min: 0.2, max: 1 (nM) from 2 assay(s)
Binding MOAD:  2OFV IC50: 0.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.301 
  • R-Value Work: 0.274 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 142.66α = 90
b = 66.89β = 112
c = 78.51γ = 90
Software Package:
Software NamePurpose
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