 |
PDBsum entry 5y9t
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Transferase
|
|
|
Title:
|
|
Crystal structure of egfr t790m mutant in complex with naquotinib
|
|
Structure:
|
|
Epidermal growth factor receptor. Chain: a. Fragment: unp residues 695-1022. Synonym: proto-oncogenE C-erbb-1,receptor tyrosine-protein kinase erbb-1. Engineered: yes. Mutation: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
|
|
Resolution:
|
|
|
3.25Å
|
R-factor:
|
0.197
|
R-free:
|
0.240
|
|
|
Authors:
|
|
S.Mimasu,Y.Tomimoto,I.Maiko,A.Yasushi,N.Tatsuya
|
|
Key ref:
|
|
T.Hirano
et al.
(2018).
Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase Inhibitor, in EGFR-Mutated Non-Small Cell Lung Cancer.
Mol Cancer Ther,
17,
740-750.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
28-Aug-17
|
Release date:
|
11-Jul-18
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P00533
(EGFR_HUMAN) -
Epidermal growth factor receptor from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
1210 a.a.
300 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
|
*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.2.7.10.1
- receptor protein-tyrosine kinase.
|
|
|
|
|
|
|
Reaction:
|
|
L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
|
|
|
|
|
|
L-tyrosyl-[protein]
|
+
|
ATP
|
=
|
O-phospho-L-tyrosyl-[protein]
|
+
|
ADP
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
Mol Cancer Ther
17:740-750
(2018)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase Inhibitor, in EGFR-Mutated Non-Small Cell Lung Cancer.
|
|
T.Hirano,
H.Yasuda,
J.Hamamoto,
S.Nukaga,
K.Masuzawa,
I.Kawada,
K.Naoki,
T.Niimi,
S.Mimasu,
H.Sakagami,
K.Soejima,
T.Betsuyaku.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Multiple epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
(EGFR-TKI) have been developed to effectively inhibit EGFR-derived signals in
non-small cell lung cancer (NSCLC). In this study, we assessed the efficacy of
EGFR-TKIs, including a novel third-generation inhibitor naquotinib (ASP8273), in
clinically relevant EGFR mutations, including L858R, exon 19 deletion,
L858R+T790M, exon 19 deletion+T790M with or without a C797S mutation, and
several exon 20 insertion mutations. Using structural analyses, we also
elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs
in EGFR exon 20 insertion mutations. The efficacy of naquotinib in cells
with L858R, exon 19 deletion and exon 19 deletion+T790M was comparable with that
of osimertinib. Interestingly, naquotinib was more potent than osimertinib for
L858R+T790M. Additionally, naquotinib and osimertinib had comparable efficacy
and a wide therapeutic window for cells with EGFR exon 20 insertions.
Structural modeling partly elucidated the mechanism of activation and
sensitivity/resistance to EGFR-TKIs in two EGFR exon 20 insertion
mutants, A767_V769dupASV and Y764_V765insHH. In summary, we have characterized
the efficacy of EGFR-TKIs for NSCLC using in vitro and structural
analyses and suggested the mechanism of activation and resistance to EGFR-TKIs
of EGFR exon 20 insertion mutations. Our findings should guide the
selection of appropriate EGFR-TKIs for the treatment of NSCLC with EGFR
mutations and help clarify the biology of EGFR exon 20 insertion
mutations. Mol Cancer Ther; 17(4); 740-50. ©2018 AACR.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
