5GNK

Crystal structure of EGFR 696-988 T790M in complex with LXX-6-34


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.177 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode.

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

(2017) J Med Chem 60: 2944-2962

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01907
  • Primary Citation of Related Structures:  
    5GNK

  • PubMed Abstract: 

    On the basis of Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-helix-out" inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC.


  • Organizational Affiliation

    High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, 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 receptor297Homo 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 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
80U
Query on 80U

Download Ideal Coordinates CCD File 
B [auth A]1-[(3R)-3-[4-azanyl-3-[3-chloranyl-4-[(1-methylimidazol-2-yl)methoxy]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
C24 H25 Cl N8 O2
IDPFQFBOJCHECD-MRXNPFEDSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
AA [auth A]
BA [auth A]
EA [auth A]
GA [auth A]
HA [auth A]
AA [auth A],
BA [auth A],
EA [auth A],
GA [auth A],
HA [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A],
R [auth A],
S [auth A],
T [auth A],
U [auth A],
V [auth A],
W [auth A],
X [auth A],
Y [auth A],
Z [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
NO3
Query on NO3

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
DA [auth A]
E [auth A]
F [auth A]
C [auth A],
D [auth A],
DA [auth A],
E [auth A],
F [auth A],
FA [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A]
NITRATE ION
N O3
NHNBFGGVMKEFGY-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
CA [auth A],
Q [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.177 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 
  • Space Group: P 42 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 106.004α = 90
b = 106.004β = 90
c = 73.791γ = 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: 2017-04-05
    Type: Initial release
  • Version 1.1: 2017-10-04
    Changes: Data collection
  • Version 1.2: 2017-12-06
    Changes: Database references
  • Version 1.3: 2023-11-08
    Changes: Data collection, Database references, Refinement description