5HCX

EGFR kinase domain mutant "TMLR" with azabenzimidazole compound 7


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor.

Chan, B.K.Hanan, E.J.Bowman, K.K.Bryan, M.C.Burdick, D.Chan, E.Chen, Y.Clausen, S.Dela Vega, T.Dotson, J.Eigenbrot, C.Elliott, R.L.Heald, R.A.Jackson, P.S.Knight, J.D.La, H.Lainchbury, M.D.Malek, S.Purkey, H.E.Schaefer, G.Schmidt, S.Seward, E.M.Sideris, S.Shao, L.Wang, S.Yeap, S.K.Yen, I.Yu, C.Heffron, T.P.

(2016) J Med Chem 59: 9080-9093

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00995
  • Primary Citation of Related Structures:  
    5HCX, 5HCY, 5HCZ

  • PubMed Abstract: 

    Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR mutant positive non-small-cell lung cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against those first generation therapeutics. Herein, we describe the lead optimization of a series of reversible, pan-mutant (L858R, del 746-750, T790M/L858R, and T790M/del 746-750 ) EGFR inhibitors. By use of a noncovalent double mutant (T790M/L858R and T790M/del 746-750 ) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del 746-750 ) were introduced through a series of structure-guided modifications. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the single and double mutants of EGFR, demonstrating target engagement in vivo and ADME-PK properties that are suitable for further evaluation. The reversible, noncovalent inhibitors described complement the covalent pan-mutant EGFR inhibitors that have shown encouraging results in recent clinical trials.


  • Organizational Affiliation

    Charles River Laboratories, 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.


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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
60B
Query on 60B

Download Ideal Coordinates CCD File 
C [auth A]~{N}-[2-(1-cyclopropylsulfonylpyrazol-4-yl)pyrimidin-4-yl]-2-methyl-1-propan-2-yl-imidazo[4,5-c]pyridin-6-amine
C20 H22 N8 O2 S
NOWVRPHFPYFSDG-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 
  • Space Group: I 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 146.744α = 90
b = 146.744β = 90
c = 146.744γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-07
    Type: Initial release
  • Version 1.1: 2016-10-26
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description