Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma.
Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma.
复制标题
DOI：
10.1002/cam4.175
复制
发表时间：
2014-02
期刊：
影响因子：
4
通讯作者：
Nakagawara, Akira
中科院分区：
文献类型：
--
作者：
Nakamura, Yohko;Suganami, Akiko;Fukuda, Mayu;Hasan, Md. Kamrul;Yokochi, Tomoki;Takatori, Atsushi;Satoh, Shunpei;Hoshino, Tyuji;Tamura, Yutaka;Nakagawara, Akira
神经母细胞瘤（NB）是儿童最常见的实体肿瘤之一，其预后仍然很差。神经营养素受体TrkB及其配体脑源性神经营养因子（BDNF）在高危NB中高水平表达，并参与定义患者的不良预后。然而，TrkB靶向治疗尚未在临床上实现。我们利用AutoDock/网格计算技术进行了计算机筛选程序，以鉴定靶向TrkB的BDNF结合结构域的新型小化合物。对于第一次筛选，在计算机中筛选了三百万合成化合物的文库，并根据对接能量进行排名。通过使用NB细胞系进一步功能性筛选排名靠前的37种化合物的细胞毒性。最终确定了7个化合物对NB细胞有杀伤作用，IC_（50）值为0.07-4.6 μmol/L。 末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）分析表明，这些分子诱导NB细胞系伴随着p53激活的凋亡。候选化合物和BDNF表现出对细胞生长、侵袭和集落形成的拮抗作用，这可能表明在TrkB的BDNF结合位点存在竞争。候选化合物在使用小鼠的异种移植物和体内毒性试验（口服和静脉内给药）中具有肿瘤抑制活性，并且没有显示出任何异常体征。使用计算机对接筛选，我们发现了针对高风险NB的新候选TrkB抑制剂，这可能导致新的抗癌药物。
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.
登录
查看更多内容
影响因子：
5.6
作者：
Chang, Max W.;Lindstrom, William;Belew, Richard K.
通讯作者：
Belew, Richard K.
影响因子：
4.4
作者：
NAKAGAWARA, A;LIU, XC;BRODEUR, GM
通讯作者：
BRODEUR, GM
影响因子：
8
作者：
Ohira, M;Kageyama, H;Nakagawara, A
通讯作者：
Nakagawara, A
影响因子：
45.3
作者：
Eggert, A;Grotzer, MA;Evans, AE
通讯作者：
Evans, AE
影响因子：
56.9
作者：
LEVIMONTALCINI, R
通讯作者：
LEVIMONTALCINI, R