4H58

BRAF in complex with compound 3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.224 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery and Optimization of a Novel Series of Potent Mutant B-Raf(V600E) Selective Kinase Inhibitors.

Vasbinder, M.M.Aquila, B.Augustin, M.Chen, H.Cheung, T.Cook, D.Drew, L.Fauber, B.P.Glossop, S.Grondine, M.Hennessy, E.Johannes, J.Lee, S.Lyne, P.Mortl, M.Omer, C.Palakurthi, S.Pontz, T.Read, J.Sha, L.Shen, M.Steinbacher, S.Wang, H.Wu, A.Ye, M.

(2013) J Med Chem 56: 1996-2015

  • DOI: https://doi.org/10.1021/jm301658d
  • Primary Citation of Related Structures:  
    4BB4, 4H58

  • PubMed Abstract: 

    B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro and in vivo. Investigations into the structure-activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-Raf(V600E) in vitro and showed preferential antiproliferative activity in mutant B-Raf(V600E) cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-Raf(V600E) A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in nonmutant B-Raf cell lines in vitro.


  • Organizational Affiliation

    Oncology iMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. melissa.vasbinder@astrazeneca.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, C
275Homo 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
10Z
Query on 10Z

Download Ideal Coordinates CCD File 
D [auth A]N-(4-{[(2-methoxyethyl)amino]methyl}phenyl)-6-(pyridin-4-yl)quinazolin-2-amine
C23 H23 N5 O
UKKAXPVDQSQDFB-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
E [auth C]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
10Z PDBBind:  4H58 IC50: 192 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.224 
  • Space Group: I 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 204.74α = 90
b = 204.74β = 90
c = 152.95γ = 90
Software Package:
Software NamePurpose
MOLREPphasing
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-02-27
    Type: Initial release
  • Version 1.1: 2013-03-27
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description