靶向间变性淋巴瘤激酶儿童神经母细胞瘤治疗药物的筛选与验证  

Screening and Verification of Therapeutic Drugs Targeting Anaplastic Lymphoma Kinase for Childhood Neuroblastoma

作　　者：刘天一 胡雪姣 张哲 胡清洋 闫文欣 东雪 李中 LIU Tianyi;HU Xuejiao;ZHANG Zhe;HU Qingyang;YAN Wenxin;DONG Xue;LI Zhong(Department of Pharmaceutics,Dalian Women and Children's Medical Group,Dalian 116012,China;College of Pharmacy,Dalian Medical University,Dalian 116044,China)

机构地区：[1]大连市妇女儿童医疗中心(集团)药剂科,大连116012 [2]大连医科大学药学院,大连116044

出　　处：《中国现代应用药学》2024年第24期3481-3487,共7页Chinese Journal of Modern Applied Pharmacy

基　　金：大连市科技创新基金项目(2023JJ13SN044)。

摘　　要：目的以间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)为靶点筛选儿童神经母细胞瘤(neuroblastoma,NB)的靶向治疗药物。方法借助计算机辅助药物的虚拟筛选技术筛选靶向结合ALK的命中化合物,通过分子动力学模拟验证命中化合物与ALK的结合能力,通过CCK-8试验验证命中化合物对NB细胞的杀伤作用,通过Western blotting试验检测命中化合物对ALK的抑制作用。结果虚拟筛选和分子动力学模拟试验发现6种命中化合物中栎草亭能够和ALK形成稳定的受体-配体二元复合物。体外细胞实验表明栎草亭能抑制ALK表达,诱导NB细胞凋亡,并对NB细胞有杀伤作用。结论栎草亭可能是治疗NB的有效候选药物。OBJECTIVE Neuroblastoma(NB)is a common extracranial solid tumor in children,accounting for about 7%−10%of childhood malignant tumors and about 15%of all childhood cancer deaths.Approximately 50%of cases are high-risk with a relatively low overall survival rate.Even with intensive myeloablative chemotherapy,recurrence is still common and fatal.Therefore,new treatment methods must be explored by targeting molecular and genetic abnormalities during tumorigenesis and disease progression.Anaplastic lymphoma kinase(ALK)is a cell surface neural receptor tyrosine kinase that is significantly expressed only in the developing embryo and neonatal brain and belongs to the insulin receptor tyrosine kinase superfamily.Studies have shown that mutations or gene amplifications of ALK are associated with NB susceptibility in 15%of patients.Studies have shown that activated ALK can promote cell growth and survival and inhibit the proliferation of NB cells.In a significant number of cases,high ALK expression is associated with a poor prognosis of NB.ALK is rarely expressed in the tissues of normal healthy people but is highly expressed in some cancer tissues.This characteristic makes ALK an ideal therapeutic target for neuroblastoma.This study is dedicated to using computer-aided drug design methods to screen for inhibitors with significant selectivity for ALK from natural products of traditional Chinese medicine,thus hopefully solving the resistance problem of existing ALK inhibitors such as crizotinib and opening up a new way for the treatment of neuroblastoma.METHODS Obtained the structures of ALK(4FOB,4FOC,and 4FOD)from the PDB database.Used the traditional Chinese medicine natural product database YaTCM as the ligand library and screen with 4FOB,4FOC and 4FOD as receptors respectively.Compounds with scores in the top 15%in the previous step entered the next round of screening.Finally,taken the intersection of the screened compounds obtained from the three virtual screenings,and the final intersection compounds were the hit co

关 键 词：间变性淋巴瘤激酶 神经母细胞瘤 计算机辅助药物设计 分子动力学模拟 

分 类 号：R969.3[医药卫生—药理学]