具有肿瘤靶向性的炔酸酯类探针分子化学构建及其调控端粒酶相关信号通路的研究

端粒酶在绝大多数恶性肿瘤中表现出活性异常增加。端粒酶活性的调控是多途径、多因素的，涉及端粒酶自身各组分的基因转录、翻译、翻译后修饰、蛋白磷酸化调节。本项目将基于前期筛选出的具有抗肿瘤活性的炔酸酯类化合物，在化合物上化学连接新型的多肽类靶向分子，构建全新的肿瘤靶向性化学小分子探针。在此基础上，多手段、多角度地来探讨上述小分子探针对端粒酶活性的调控及其作用机制，以及对相关信号转导通路的影响。本项目的开展将有望获得一类端粒酶研究新型化学探针分子，并为抗癌药物的新机制、新途径的研究提供理论依据。同时，为临床的肿瘤治疗提供全新的、高效、低毒副作用的化疗药物的先导化合物。

Telomerase showed an aberrant activity increase in most malignant tumors. In mammalian cells, telomerase activity is regulated in different ways, related with the gene transcription, translation,,post-translational modifications and protein phosphorylation of the components of telomerase. In previous study, we screened the chemical library, finding a group of acetylenic acid ester compounds which showed potential inhibitory effect on telomerase activity and remarkable antitumor activity. In this study, we will link the compounds with a peptide vector targeting tumor cells by chemical synthesis. Using them, we will investigate the mechanisms of acetylenic acid ester compounds in telomerase activity regulation and their influence on associated cellular signal transduction pathways. Our aims are: 1) to obtain a novel class of small molecule probes which can be used to study telomerase and telomerase-associated mechanisms in tumor pathology; 2) to provide lead compounds with high efficacy and low toxicity for clinical cancer therapy.