title: Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma.
abstract: 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 μmol/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.
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba, 260-8717, Japan.
authors.forename: Yohko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Akiko
authors.initials: A
authors.lastname: Suganami
authors.forename: Mayu
authors.initials: M
authors.lastname: Fukuda
authors.forename: Md Kamrul
authors.initials: MK
authors.lastname: Hasan
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yokochi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takatori
authors.forename: Shunpei
authors.initials: S
authors.lastname: Satoh
authors.forename: Tyuji
authors.initials: T
authors.lastname: Hoshino
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tamura
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008562:Membrane Glycoproteins; D051379:Mice; D062105:Molecular Docking Simulation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011494:Protein Kinases / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries
chemical_list: D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D054852:Small Molecule Libraries; C579455:BDNF protein, human; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human
keywords: BDNF; TrkB; drug discovery; in silico simulations; neuroblastoma