具有诱导细胞巨泡化死亡等多重作用机制的抗神经胶质瘤药物研究

Glioblastoma is the most frequent primary tumor in the central nervous system. The current standard care for newly diagnosed glioblastoma is.surgical resection, followed by adjuvant radiotherapy and chemotherapy. However，the effectness of this remedy was weakened by drug resistance and adverse reactions. Gliblastoma is difficult to cure for its very complex mechanism. The patients may have a benign prognosis and prolong their median survival time after a multi-target drug treatment by synergic effects. In our recent research, series of pyrrolo[2,3,4-kl]acridin-1-one derivatives were designed and synthesized after combine the skeleton characters of thioridazine, 9-amino-acrdine, and lucanthone, the lead compound. Several compounds show superior anti-glioblastoma activity to both lucanthone and temozolomide. These compounds with novel scaffold promote apoptosis by dual inhibiting DNA topoisomerase I and II, moreover, induce a novel cell death, muthuosis, by which reverse the multi-drug resistance. These compounds are also proved to bind to intergrin CD11b/CD18, thus prevent tumor migration and metastasis by blocking the tumor-associated macrophage recruting. This project aims to find potent anti-glioblastoma agents by synergic mechanism study in the arise, development, and metastasis of cancer after further structure modification, in vitro and in vivo assays.

神经胶质瘤是中枢神经系统发病率最高的恶性肿瘤，标准治疗方案是术后进行放疗联合替莫唑胺化疗，但耐药性、不良反应等均影响治疗效果。胶质瘤发病机制复杂，多靶点药物通过多重机制协同作用，有望大幅改善患者预后、延长生存期。在前期工作中，以硫蒽酮为先导化合物，融合硫利达嗪及氨吖啶的结构骨架特征，设计并合成了系列吡咯并[2,3,4-kl]吖啶-1（2H）-酮衍生物，从中发现了多个化合物体外抗胶质瘤活性优于先导物硫蒽酮和临床用药替莫唑胺。发现的新结构化合物同时抑制DNA 拓扑异构酶I和II，促进胶质瘤细胞凋亡；还显著诱导巨泡式死亡，此新颖机制可以逆转肿瘤耐药性；还作用于整合素CD11b/CD18，有望通过抑制募集肿瘤相关巨噬细胞，发挥抗肿瘤侵袭、转移作用。本课题将继续优化结构和活性筛选，研究该类药物在抑制肿瘤发生、演进、转移等方面发挥的协同机制，为发现具有多重作用机制的抗胶质瘤药物奠定基础。

神经胶质瘤年发病29.7万人，近20年来最好的抗胶质瘤药物为替莫唑胺，替莫唑胺耐药后病人面临无药可用的窘境。本项目发现了具有国内、国际知识产权、多种新颖作用机制的抗肿瘤候选药物，编号为LS-1-2F，对多种肿瘤细胞株的增值有非常显著的抑制活性；显著诱导肿瘤细胞发生巨泡式死亡，并通过该新颖机制逆转多重耐药性；在很低浓度下可以高效抑制肿瘤干细胞的自我更新，同时显著下调其8种干性标志物的水平，并直接杀伤CD133+肿瘤干细胞。.鉴于LS-1-2F具有独特的逆转肿瘤耐药机理和脑组织分布高的特点，开展了针对耐药神经胶质瘤的研究。发现该药物在口服安全剂量下，抑制耐药蛋白MGMT的表达，对替莫唑胺耐药的神经胶质瘤具有优异的体外、体内抑制活性，该药物非常有希望应用于晚期耐药胶质瘤患者。.该项目已获得中国、美国、欧洲、日本、澳大利亚等国专利证书，知识产权已转让给一家医药企业进行临床前研究，目前正在开展原料药中试工艺研究。预计2021年完成临床前各项研究资料，并获得国家药监局临床试验许可。

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