5UR1

FGFR1 kinase domain complex with SN37333 in reversible binding mode


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.230 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

2-Oxo-3, 4-dihydropyrimido[4, 5-d]pyrimidinyl derivatives as new irreversible pan fibroblast growth factor receptor (FGFR) inhibitors.

Li, X.Guise, C.P.Taghipouran, R.Yosaatmadja, Y.Ashoorzadeh, A.Paik, W.K.Squire, C.J.Jiang, S.Luo, J.Xu, Y.Tu, Z.C.Lu, X.Ren, X.Patterson, A.V.Smaill, J.B.Ding, K.

(2017) Eur J Med Chem 135: 531-543

  • DOI: https://doi.org/10.1016/j.ejmech.2017.04.049
  • Primary Citation of Related Structures:  
    5UR1

  • PubMed Abstract: 

    A series of 2-oxo-3, 4-dihydropyrimido[4,5-d]-pyrimidinyl derivatives were designed and synthesized as new irreversible inhibitors of the FGFR family. One of the most promising compounds 2l potently inhibited FGFR1/2/3 with IC 50 values of 1.06, 0.84 and 5.38 nM, respectively, whereas its potency against FGFR4 was diminished by an order of magnitude. Compound 2l strongly suppresses the proliferation of FGFR1-amplified H520 non-small cell lung cancer cells, FGFR2-amplified SUM52 breast cancer cells and FGFR3-amplified SW780 bladder cancer cells with low nanomolar IC 50 values, but was significantly less potent against four FGFR-negative cancer cell lines, with low micromolar IC 50 values. Biological investigation also confirmed the irreversible binding of the molecule with the FGFR1-3 target kinases. Compound 2l may serve as a promising new lead for further anticancer drug discovery.


  • Organizational Affiliation

    Guangzhou Institutes of Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Chinese Academy of Sciences, No.190 Kaiyuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fibroblast growth factor receptor 1
A, B
311Homo 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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
YY9
Query on YY9

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{1-[4-(dimethylamino)but-2-enoyl]piperidin-4-yl}-7-(phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one
C31 H35 Cl2 N7 O4
YHIGPAIFBVOPKV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
YY9 BindingDB:  5UR1 IC50: min: 0.84, max: 1.1 (nM) from 2 assay(s)
Binding MOAD:  5UR1 IC50: 1.06 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.230 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 213.05α = 90
b = 51.783β = 106.87
c = 66.07γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-31
    Type: Initial release
  • Version 1.1: 2023-10-04
    Changes: Data collection, Database references, Refinement description