5EDQ

EGFR kinase (T790M/L858R) with inhibitor compound 15: ~{N}-(7-chloranyl-1~{H}-indazol-3-yl)-7,7-dimethyl-2-(1~{H}-pyrazol-4-yl)-5~{H}-furo[3,4-d]pyrimidin-4-amine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.209 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

4-Aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase.

Hanan, E.J.Baumgardner, M.Bryan, M.C.Chen, Y.Eigenbrot, C.Fan, P.Gu, X.H.La, H.Malek, S.Purkey, H.E.Schaefer, G.Schmidt, S.Sideris, S.Yen, I.Yu, C.Heffron, T.P.

(2016) Bioorg Med Chem Lett 26: 534-539

  • DOI: https://doi.org/10.1016/j.bmcl.2015.11.078
  • Primary Citation of Related Structures:  
    5EDP, 5EDQ, 5EDR

  • PubMed Abstract: 

    The treatment of epidermal growth factor receptor (EGFR)-driven non-small cell lung cancers with the T790M resistance mutation remains a significant unmet medical need. We report the identification of 4-aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of EGFR, with excellent activity against the T790M resistance double mutants and initial single activating mutants. Using an optimization strategy focused on structure-based design and improving PK properties through metabolite identification, we obtained advanced leads with high oral exposure.


  • Organizational Affiliation

    Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Epidermal growth factor receptor331Homo sapiensMutation(s): 5 
Gene Names: EGFRERBBERBB1HER1
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00533 (Homo sapiens)
Explore P00533 
Go to UniProtKB:  P00533
PHAROS:  P00533
GTEx:  ENSG00000146648 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00533
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5N3
Query on 5N3

Download Ideal Coordinates CCD File 
B [auth A]~{N}-(7-chloranyl-1~{H}-indazol-3-yl)-7,7-dimethyl-2-(1~{H}-pyrazol-4-yl)-5~{H}-furo[3,4-d]pyrimidin-4-amine
C18 H16 Cl N7 O
OWTUZFHMSVAQSQ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5N3 BindingDB:  5EDQ Ki: min: 0.4, max: 2 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.209 
  • Space Group: I 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 148.919α = 90
b = 148.919β = 90
c = 148.919γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-12-02
    Type: Initial release
  • Version 1.1: 2015-12-23
    Changes: Database references
  • Version 1.2: 2016-01-20
    Changes: Database references
  • Version 1.3: 2024-03-06
    Changes: Data collection, Database references, Derived calculations