PMID- 24403123
OWN - NLM
STAT- MEDLINE
DCOM- 20141125
LR  - 20211021
IS  - 2045-7634 (Electronic)
IS  - 2045-7634 (Print)
IS  - 2045-7634 (Linking)
VI  - 3
IP  - 1
DP  - 2014 Feb
TI  - Identification of novel candidate compounds targeting TrkB to induce apoptosis in 
      neuroblastoma.
PG  - 25-35
LID - 10.1002/cam4.175 [doi]
AB  - Neuroblastoma (NB) is one of the most frequent solid tumors in children and its 
      prognosis is still poor. The neurotrophin receptor TrkB and its ligand 
      brain-derived neurotrophic factor (BDNF) are expressed at high levels in 
      high-risk NBs and are involved in defining the poor prognosis of the patients. 
      However, the TrkB targeting therapy has never been realized in the clinic. We 
      performed an in silico screening procedure utilizing an AutoDock/grid computing 
      technology in order to identify novel small chemical compounds targeting the 
      BDNF-binding domain of TrkB. For the first screening, a library of three million 
      synthetic compounds was screened in silico and was ranked according to the 
      Docking energy. The top-ranked 37 compounds were further functionally screened 
      for cytotoxicity by using NB cell lines. We have finally identified seven 
      compounds that kill NB cells with the IC50 values of 0.07-4.6 mumol/L. The 
      terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed 
      that these molecules induce apoptosis accompanied by p53 activation in NB cell 
      lines. The candidate compounds and BDNF demonstrated an antagonistic effect on 
      cell growth, invasion, and colony formation, possibly suggesting competition at 
      the BDNF-binding site of TrkB. The candidate compounds had tumor-suppressive 
      activity in xenograft and in vivo toxicity tests (oral and intravenous 
      administrations) using mice, and did not show any abnormal signs. Using in silico 
      Docking screening we have found new candidate TrkB inhibitors against high-risk 
      NBs, which could lead to new anti-cancer drugs.
CI  - (c) 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
FAU - Nakamura, Yohko
AU  - Nakamura Y
AD  - Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center 
      Research Institute, Chiba, 260-8717, Japan.
FAU - Suganami, Akiko
AU  - Suganami A
FAU - Fukuda, Mayu
AU  - Fukuda M
FAU - Hasan, Md Kamrul
AU  - Hasan MK
FAU - Yokochi, Tomoki
AU  - Yokochi T
FAU - Takatori, Atsushi
AU  - Takatori A
FAU - Satoh, Shunpei
AU  - Satoh S
FAU - Hoshino, Tyuji
AU  - Hoshino T
FAU - Tamura, Yutaka
AU  - Tamura Y
FAU - Nakagawara, Akira
AU  - Nakagawara A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140101
PL  - United States
TA  - Cancer Med
JT  - Cancer medicine
JID - 101595310
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Small Molecule Libraries)
RN  - 7171WSG8A2 (BDNF protein, human)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.10.1 (tropomyosin-related kinase-B, human)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Apoptosis/drug effects
MH  - Brain-Derived Neurotrophic Factor/*biosynthesis/genetics
MH  - Cell Line, Tumor
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Membrane Glycoproteins
MH  - Mice
MH  - Molecular Docking Simulation
MH  - Neuroblastoma/*drug therapy/genetics/pathology
MH  - Protein Kinases/biosynthesis/chemistry/*genetics
MH  - Protein-Tyrosine Kinases
MH  - Receptor, trkB
MH  - Signal Transduction/drug effects
MH  - Small Molecule Libraries
PMC - PMC3930387
OTO - NOTNLM
OT  - BDNF
OT  - TrkB
OT  - drug discovery
OT  - in silico simulations
OT  - neuroblastoma
EDAT- 2014/01/10 06:00
MHDA- 2014/12/15 06:00
PMCR- 2014/02/01
CRDT- 2014/01/10 06:00
PHST- 2013/06/20 00:00 [received]
PHST- 2013/10/31 00:00 [revised]
PHST- 2013/11/01 00:00 [accepted]
PHST- 2014/01/10 06:00 [entrez]
PHST- 2014/01/10 06:00 [pubmed]
PHST- 2014/12/15 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - 10.1002/cam4.175 [doi]
PST - ppublish
SO  - Cancer Med. 2014 Feb;3(1):25-35. doi: 10.1002/cam4.175. Epub 2014 Jan 1.