4ZSA

Crystal structure of FGFR1 kinase domain in complex with 7n


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.206 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold.

Liu, J.Peng, X.Dai, Y.Zhang, W.Ren, S.Ai, J.Geng, M.Li, Y.

(2015) Org Biomol Chem 13: 7643-7654

  • DOI: https://doi.org/10.1039/c5ob00778j
  • Primary Citation of Related Structures:  
    4ZSA

  • PubMed Abstract: 

    Fibroblast growth factor receptor (FGFR) is a potential target for cancer therapy. Based on the structure of AZD4547 and NVPBGJ-398, we designed novel 1H-indazol-3-amine scaffold derivatives by utilizing scaffold hopping and molecular hybridization strategies. Consequently, twenty-eight new compounds were synthesized and evaluated for their inhibitory activity against FGFR1. Compound 7n bearing a 6-(3-methoxyphenyl)-1H-indazol-3-amine scaffold was first identified as a potent FGFR1 inhibitor, with good enzymatic inhibition (IC50 = 15.0 nM) and modest cellular inhibition (IC50 = 642.1 nM). The crystal structure of 7n bound to FGFR1 was obtained, which might provide a new basis for potent inhibitor design. Further structural optimization revealed that compound 7r stood out as the most potent FGFR1 inhibitor with the best enzyme inhibitory (IC50 = 2.9 nM) and cellular activity (IC50 = 40.5 nM).


  • Organizational Affiliation

    School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. liyx417@fudan.edu.cn.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fibroblast growth factor receptor 1
A, B
308Homo sapiensMutation(s): 2 
Gene Names: FGFR1BFGFRCEKFGFBRFLGFLT2HBGFR
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P11362 (Homo sapiens)
Explore P11362 
Go to UniProtKB:  P11362
PHAROS:  P11362
GTEx:  ENSG00000077782 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11362
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4UT
Query on 4UT

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
4-(4-ethylpiperazin-1-yl)-N-[6-(3-methoxyphenyl)-2H-indazol-3-yl]benzamide
C27 H29 N5 O2
LDEZCHXBGZHBFD-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4UT Binding MOAD:  4ZSA IC50: 15 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.206 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 209.91α = 90
b = 57.181β = 107.47
c = 65.55γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
HKL-2000data scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
Cootdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-06-17
    Type: Initial release
  • Version 1.1: 2015-07-22
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description, Source and taxonomy