首页> 美国卫生研究院文献>Cancer Medicine >Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma
【2h】

Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma

机译:鉴定靶向TrkB诱导神经母细胞瘤凋亡的新型候选化合物

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务,本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文,但由于OA文献来源多样且变更频繁,仍可能出现获取不到、文献不完整或与标题不符等情况,如果获取不到我们将提供退款服务。请知悉。
获取外文期刊封面目录资料

摘要

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.
机译:神经母细胞瘤(NB)是儿童中最常见的实体瘤之一,其预后仍然很差。神经营养蛋白受体TrkB及其配体脑源性神经营养因子(BDNF)在高风险NB中高水平表达,并参与确定患者的不良预后。然而,在临床上尚未实现TrkB靶向疗法。我们使用AutoDock /网格计算技术进行了计算机筛选程序,以鉴定靶向TrkB BDNF结合域的新型小化学化合物。对于第一次筛选,对300万种合成化合物的库进行了计算机筛选,并根据Docking能量对其进行了排名。使用NB细胞系进一步筛选了排名靠前的37种化合物的细胞毒性。我们最终确定了七种杀死NB细胞的化合物,其IC50值为0.07–4.6μmol / L。末端脱氧核苷酸转移酶dUTP缺口末端标记(TUNEL)分析表明,这些分子在NB细胞系中诱导凋亡并伴随p53活化。候选化合物和BDNF对细胞生长,侵袭和集落形成具有拮抗作用,可能暗示在TrkB的BDNF结合位点竞争。候选化合物在使用小鼠的异种移植和体内毒性试验(口服和静脉内给药)中具有肿瘤抑制活性,并且未显示任何异常体征。通过计算机对接筛选,我们发现了针对高风险NB的新型候选TrkB抑制剂,这可能会导致新的抗癌药物。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号