6YI8 | pdb_00006yi8

HUMAN FGFR4 KINASE DOMAIN (447-753) IN COMPLEX WITH ROBLITINIB


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.13 Å
  • R-Value Free: 
    0.231 (Depositor), 0.200 (DCC) 
  • R-Value Work: 
    0.196 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 
    0.198 (Depositor) 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted FGFClick on this verticalbar to view details

This is version 1.3 of the entry. See complete history


Literature

Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4.

Fairhurst, R.A.Knoepfel, T.Buschmann, N.Leblanc, C.Mah, R.Todorov, M.Nimsgern, P.Ripoche, S.Niklaus, M.Warin, N.Luu, V.H.Madoerin, M.Wirth, J.Graus-Porta, D.Weiss, A.Kiffe, M.Wartmann, M.Kinyamu-Akunda, J.Sterker, D.Stamm, C.Adler, F.Buhles, A.Schadt, H.Couttet, P.Blank, J.Galuba, I.Trappe, J.Voshol, J.Ostermann, N.Zou, C.Berghausen, J.Del Rio Espinola, A.Jahnke, W.Furet, P.

(2020) J Med Chem 63: 12542-12573

  • DOI: https://doi.org/10.1021/acs.jmedchem.0c01019
  • Primary Citation of Related Structures:  
    6YI8

  • PubMed Abstract: 

    FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.


  • Organizational Affiliation

    Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fibroblast growth factor receptor 4
A, B
307Homo sapiensMutation(s): 0 
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P22455 (Homo sapiens)
Explore P22455 
Go to UniProtKB:  P22455
PHAROS:  P22455
GTEx:  ENSG00000160867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22455
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FGF (Subject of Investigation/LOI)
Query on FGF

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
N-[5-cyano-4-(2-methoxyethylamino)pyridin-2-yl]-7-methanoyl-6-[(4-methyl-2-oxidanylidene-piperazin-1-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide
C25 H30 N8 O4
BHKDKKZMPODMIQ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A],
H [auth B],
I [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
FGF BindingDB:  6YI8 IC50: min: 1.3, max: 12 (nM) from 8 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.13 Å
  • R-Value Free:  0.231 (Depositor), 0.200 (DCC) 
  • R-Value Work:  0.196 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 0.198 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 183.707α = 90
b = 67.198β = 90
c = 53.114γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
BUSTERrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
Cootmodel building

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted FGFClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-09-30
    Type: Initial release
  • Version 1.1: 2020-11-25
    Changes: Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description, Structure summary
  • Version 1.3: 2024-10-09
    Changes: Structure summary