3Q96

B-Raf kinase domain in complex with a tetrahydronaphthalene inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.288 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.233 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Design and optimization of potent and orally bioavailable tetrahydronaphthalene raf inhibitors.

Gould, A.E.Adams, R.Adhikari, S.Aertgeerts, K.Afroze, R.Blackburn, C.Calderwood, E.F.Chau, R.Chouitar, J.Duffey, M.O.England, D.B.Farrer, C.Forsyth, N.Garcia, K.Gaulin, J.Greenspan, P.D.Guo, R.Harrison, S.J.Huang, S.C.Iartchouk, N.Janowick, D.Kim, M.S.Kulkarni, B.Langston, S.P.Liu, J.X.Ma, L.T.Menon, S.Mizutani, H.Paske, E.Renou, C.C.Rezaei, M.Rowland, R.S.Sintchak, M.D.Smith, M.D.Stroud, S.G.Tregay, M.Tian, Y.Veiby, O.P.Vos, T.J.Vyskocil, S.Williams, J.Xu, T.Yang, J.J.Yano, J.Zeng, H.Zhang, D.M.Zhang, Q.Galvin, K.M.

(2011) J Med Chem 54: 1836-1846

  • DOI: https://doi.org/10.1021/jm101479y
  • Primary Citation of Related Structures:  
    3Q96

  • PubMed Abstract: 

    Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.


  • Organizational Affiliation

    Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States. sandy.gould@mpi.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase B-raf
A, B
282Homo sapiensMutation(s): 0 
Gene Names: BRAFBRAF1RAFB1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P15056 (Homo sapiens)
Explore P15056 
Go to UniProtKB:  P15056
PHAROS:  P15056
GTEx:  ENSG00000157764 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP15056
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0NF
Query on 0NF

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(2S)-N-[3-(2-aminopropan-2-yl)-5-(trifluoromethyl)phenyl]-7-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide
C29 H29 F3 N4 O3
NHVJQLRLGGPUJY-KRWDZBQOSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0NF PDBBind:  3Q96 IC50: 2.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.288 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.233 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.029α = 90
b = 94.029β = 90
c = 165.264γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-03-23
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations