3IDP

B-Raf V600E kinase domain in complex with an aminoisoquinoline inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.201 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Selective inhibitors of the mutant B-raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline.

Smith, A.L.Demorin, F.F.Paras, N.A.Huang, Q.Petkus, J.K.Doherty, E.M.Nixey, T.Kim, J.L.Whittington, D.A.Epstein, L.F.Lee, M.R.Rose, M.J.Babij, C.Fernando, M.Hess, K.Le, Q.Beltran, P.Carnahan, J.

(2009) J Med Chem 52: 6189-6192

  • DOI: https://doi.org/10.1021/jm901081g
  • Primary Citation of Related Structures:  
    3IDP

  • PubMed Abstract: 

    The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. adrians@amgen.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
B-Raf proto-oncogene serine/threonine-protein kinaseA [auth B],
B [auth A]
300Homo sapiensMutation(s): 1 
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
L1E
Query on L1E

Download Ideal Coordinates CCD File 
C [auth B],
D [auth A]
N~1~-(4-chlorophenyl)-6-methyl-N~5~-[3-(7H-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine
C26 H19 Cl N8
KKVYYGGCHJGEFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
L1E BindingDB:  3IDP Ki: 1 (nM) from 1 assay(s)
IC50: min: 1.6, max: 2 (nM) from 2 assay(s)
EC50: 1.8 (nM) from 1 assay(s)
PDBBind:  3IDP IC50: 1.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.201 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.457α = 90
b = 93.457β = 90
c = 166.679γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
DENZOdata reduction
EPMRphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-10-06
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Refinement description, Version format compliance
  • Version 1.2: 2021-10-13
    Changes: Database references, Derived calculations
  • Version 1.3: 2023-09-06
    Changes: Data collection, Refinement description