5GTY

Crystal structure of EGFR 696-1022 T790M in complex with LXX-6-26


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.14 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.257 
  • R-Value Observed: 0.258 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode.

Hu, C.Wang, A.Wu, H.Qi, Z.Li, X.Yan, X.E.Chen, C.Yu, K.Zou, F.Wang, W.Wang, W.Wu, J.Liu, J.Wang, B.Wang, L.Ren, T.Zhang, S.Yun, C.H.Liu, J.Liu, Q.

(2017) Oncotarget 8: 18359-18372

  • DOI: https://doi.org/10.18632/oncotarget.15443
  • Primary Citation of Related Structures:  
    5GTY

  • PubMed Abstract: 

    EGFR T790M mutation accounts for about 40-55% drug resistance for the first generation EGFR kinase inhibitors in the NSCLC. Starting from ibrutinib, a highly potent irreversible BTK kinase inhibitor, which was also found to be moderately active to EGFR T790M mutant, we discovered a highly potent irreversible EGFR inhibitor CHMFL-EGFR-26, which is selectively potent against EGFR mutants including L858R, del19, and L858R/T790M. It displayed proper selectivity window between the EGFR mutants and the wide-type. CHMFL-EGFR-26 exhibited good selectivity profile among 468 kinases/mutants tested (S score (1)=0.02). In addition, X-ray crystallography revealed a distinct "DFG-in" and "cHelix-out" inactive binding mode between CHMFL-EGFR-26 and EGFR T790M protein. The compound showed highly potent anti-proliferative efficacy against EGFR mutant but not wide-type NSCLC cell lines through effective inhibition of the EGFR mediated signaling pathway, induction of apoptosis and arresting of cell cycle progression. CHMFL-EGFR-26 bore acceptable pharmacokinetic properties and demonstrated dose-dependent tumor growth suppression in the H1975 (EGFR L858R/T790M) and PC-9 (EGFR del19) inoculated xenograft mouse models. Currently CHMFL-EGFR-26 is undergoing extensive pre-clinical evaluation for the clinical trial purpose.


  • Organizational Affiliation

    High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Epidermal growth factor receptor331Homo sapiensMutation(s): 1 
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
816
Query on 816

Download Ideal Coordinates CCD File 
I [auth A]
J [auth B]
K [auth D]
L [auth E]
M [auth F]
I [auth A],
J [auth B],
K [auth D],
L [auth E],
M [auth F],
N [auth G],
P [auth H],
T [auth C]
1-[(3R)-3-[4-azanyl-3-[3-chloranyl-4-[(6-methylpyridin-2-yl)methoxy]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
C26 H26 Cl N7 O2
IQSSEXXITFEXLL-LJQANCHMSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
O [auth G],
Q [auth H],
R [auth H],
S [auth H]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.14 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.257 
  • R-Value Observed: 0.258 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 117.427α = 90
b = 71.796β = 103.53
c = 152.53γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
DENZOdata reduction
HKL-3000data 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: 2017-09-06
    Type: Initial release
  • Version 1.1: 2017-10-04
    Changes: Data collection
  • Version 1.2: 2017-11-29
    Changes: Database references
  • Version 1.3: 2023-11-08
    Changes: Data collection, Database references, Refinement description