3VNT

Crystal Structure of the Kinase domain of Human VEGFR2 with a [1,3]thiazolo[5,4-b]pyridine derivative


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.151 
  • R-Value Observed: 0.153 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds

Okaniwa, M.Hirose, M.Imada, T.Ohashi, T.Hayashi, Y.Miyazaki, T.Arita, T.Yabuki, M.Kakoi, K.Kato, J.Takagi, T.Kawamoto, T.Yao, S.Sumita, A.Tsutsumi, S.Tottori, T.Oki, H.Sang, B.C.Yano, J.Aertgeerts, K.Yoshida, S.Ishikawa, T.

(2012) J Med Chem 55: 3452-3478

  • DOI: https://doi.org/10.1021/jm300126x
  • Primary Citation of Related Structures:  
    3VNT, 4DBN

  • PubMed Abstract: 

    To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.


  • Organizational Affiliation

    Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. masanori.okaniwa@takeda.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Vascular endothelial growth factor receptor 2318Homo sapiensMutation(s): 0 
Gene Names: KDRFLK1VEGFR2
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P35968 (Homo sapiens)
Explore P35968 
Go to UniProtKB:  P35968
PHAROS:  P35968
GTEx:  ENSG00000128052 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35968
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0JA
Query on 0JA

Download Ideal Coordinates CCD File 
B [auth A]2-chloro-3-(1-cyanocyclopropyl)-N-[5-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]benzamide
C27 H19 Cl F N5 O3 S
MDPMAXSABUPRJI-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0JA Binding MOAD:  3VNT IC50: 2.2 (nM) from 1 assay(s)
PDBBind:  3VNT IC50: 2.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.151 
  • R-Value Observed: 0.153 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 135.615α = 90
b = 56.618β = 94.88
c = 51.819γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2012-04-11 
  • Deposition Author(s): Oki, H.

Revision History  (Full details and data files)

  • Version 1.0: 2012-04-11
    Type: Initial release
  • Version 1.1: 2013-08-07
    Changes: Database references
  • Version 1.2: 2024-03-20
    Changes: Data collection, Database references, Derived calculations