PMID- 22607878
OWN - NLM
STAT- MEDLINE
DCOM- 20121210
LR  - 20181201
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Linking)
VI  - 20
IP  - 12
DP  - 2012 Jun 15
TI  - Identification of novel drug-resistant EGFR mutant inhibitors by in silico 
      screening using comprehensive assessments of protein structures.
PG  - 3756-67
LID - 10.1016/j.bmc.2012.04.042 [doi]
AB  - EGFR is a target protein for the treatment of non small cell lung cancer (NSCLC). 
      The mutations associated with the activation of EGFR kinase activity, such as 
      L858R and G719S, destabilize the inactive conformation of EGFR and are closely 
      linked with the development of NSCLC. The additional T790M mutation reportedly 
      causes drug resistance against the commercially available EGFR inhibitors, 
      gefitinib and erlotinib. In this study, we searched for novel G719S/T790M EGFR 
      inhibitors by a new in silico screening strategy, using two datasets. The results 
      of in silico screening using protein-ligand docking are affected by the selection 
      of 3D structure of the target protein. As the first strategy, we chose the 3D 
      structures for in silico screening by test dockings using the G719S/T790M crystal 
      structure, its molecular dynamics snapshots, and known inhibitors of the 
      drug-resistant EGFR. In the second strategy, we selected the 3D structures by 
      test dockings using all of the EGFR structures, regardless of the mutations, and 
      all of the known EGFR inhibitors. Using each of the 3D structures selected by the 
      strategies, 1000 compounds were chosen from the 71,588 compounds. Kinase assays 
      identified 15 G719S/T790M EGFR inhibitors, including two compounds with novel 
      scaffolds. Analyses of their structure-activity relationships revealed that 
      interactions with the mutated Met790 residue specifically increase the inhibitory 
      activity against G719S/T790M EGFR.
CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
FAU - Sato, Tomohiro
AU  - Sato T
AD  - Department of Biophysics and Biochemistry, Graduate School of Science, The 
      University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
FAU - Watanabe, Hisami
AU  - Watanabe H
FAU - Tsuganezawa, Keiko
AU  - Tsuganezawa K
FAU - Yuki, Hitomi
AU  - Yuki H
FAU - Mikuni, Junko
AU  - Mikuni J
FAU - Yoshikawa, Seiko
AU  - Yoshikawa S
FAU - Kukimoto-Niino, Mutsuko
AU  - Kukimoto-Niino M
FAU - Fujimoto, Takako
AU  - Fujimoto T
FAU - Terazawa, Yumiko
AU  - Terazawa Y
FAU - Wakiyama, Motoaki
AU  - Wakiyama M
FAU - Kojima, Hirotatsu
AU  - Kojima H
FAU - Okabe, Takayoshi
AU  - Okabe T
FAU - Nagano, Tetsuo
AU  - Nagano T
FAU - Shirouzu, Mikako
AU  - Shirouzu M
FAU - Yokoyama, Shigeyuki
AU  - Yokoyama S
FAU - Tanaka, Akiko
AU  - Tanaka A
FAU - Honma, Teruki
AU  - Honma T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120427
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Ligands)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Drug Evaluation, Preclinical/*methods
MH  - Drug Resistance, Neoplasm/*drug effects/*genetics
MH  - ErbB Receptors/*antagonists & inhibitors/chemistry/genetics/metabolism
MH  - Humans
MH  - Ligands
MH  - Models, Molecular
MH  - Molecular Dynamics Simulation
MH  - Molecular Structure
MH  - *Mutation
MH  - Protein Kinase Inhibitors/*analysis/chemistry/*pharmacology
MH  - Structure-Activity Relationship
EDAT- 2012/05/23 06:00
MHDA- 2012/12/12 06:00
CRDT- 2012/05/22 06:00
PHST- 2012/03/14 00:00 [received]
PHST- 2012/04/20 00:00 [revised]
PHST- 2012/04/21 00:00 [accepted]
PHST- 2012/05/22 06:00 [entrez]
PHST- 2012/05/23 06:00 [pubmed]
PHST- 2012/12/12 06:00 [medline]
AID - S0968-0896(12)00326-4 [pii]
AID - 10.1016/j.bmc.2012.04.042 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2012 Jun 15;20(12):3756-67. doi: 10.1016/j.bmc.2012.04.042. Epub 
      2012 Apr 27.