具有肿瘤细胞/肿瘤血管内皮细胞双重靶向性的前列腺特异性膜蛋白（PSMA）靶向抗肿瘤药物和具有增殖抑制/血管破坏双重活性的微管蛋白秋水仙碱结合部位抑制剂（CBSI）是近年来广受关注的热点研究领域。为解决上述领域中“PSMA靶向化合物结构合理性”和“CBSI靶向性”等科学问题，首次提出“PSMA靶向CBSI”这一原创性概念，采用基于片段的计算机辅助药物设计方法，优选小分子PSMA配体作为靶向基团、PSMA选择性降解链作为连接链、本课题组前期研制的增殖抑制/血管破坏双重活性CBSI作为活性基团，完成“PSMA靶向CBSI”的设计。完成目标化合物的合成、纯化与表征，并考察目标化合物的双重活性、双重靶向性、代谢稳定性、初步毒性等成药特性。发现结构新、活性强、毒性低、靶向性突出的“PSMA靶向CBSI”，阐明“PSMA靶向CBSI”的构效关系，为创制拥有自主知识产权的靶向性抗肿瘤新药奠定基础。

Both prostate-specific membrane antigen (PSMA) targeted antitumor agents and colchicine binding site inhibitors (CBSI) have caught increasing attention in recent years, due chiefly to their dual tumor cell/tumor vascular endothelial cell targeting effects and dual proliferation-inhibiting/vascular-disrupting activities, respectively. To overcome the scientific problems including structural rationality of the PSMA targeted agents and targeting efficiency of CBSI in the fields above, a set of PSMA-targeted CBSI, a novel type of targeting antitumor agents, are developed via fragment-based drug design strategy utilizing small-molecule PSMA ligands as the targeting moieties, the PSMA-specific spacers as the linkers, and the CBSI developed by our group as the active moieties. These PSMA-targeted CBSI will be synthesized, purified and characterized. The potential druggability of the PSMA-targeted CBSI, including dual activity, dual targeting effect, mechanism of action, metabolic stability and preliminary toxicity, will be evaluated. The completion of this project will provide some novel “PSMA-targeted CBSI” with potent antitumor activity, high targeting effect and low toxicity, led to a better understanding of the structure-activity relationship, and lay the foundation for the development of next generation of tumor-targeted drugs with independent intellectual property rights.