基于结构生物学的Tubulysin衍生物的设计、合成及抗肿瘤活性研究

抗体-药物偶联物（Antibody-drug conjugates, ADC）是将强效的化学药物（弹头）与抗体通过化学方法偶联得到的新一代靶向药物，充分发挥了抗体的靶向性与化学药物的高效性。Tubulysins是源于粘细菌中的一类非天然氨基酸组成的四肽化合物，可抑制微管聚合，抗肿瘤活性极强（IC50﹤1nM），有成为新型ADC “弹头”的潜力。然而，其面临天然来源少、合成难等问题。前期研究中，我们解析了Tubulysin M-微管蛋白的晶体结构，深入揭示了其分子药理学作用机制，总结了Tubulysins关键的构效关系。基于结构生物学的指导，本项目拟按照“弹头”的要求设计并合成一系列新的Tubulysin衍生物，筛选出活性高和稳定性好的新型Tubulysin衍生物，再与抗HER2突变抗体定向偶联后进行抗肿瘤药理学研究，最终获得具有自主知识产权的新型“弹头”，为ADC药物的研发奠定基础。

Antibody-drug conjugates (ADCs) is a novel targeted drug, which is obtained by chemical method coupling potent chemical compound with antibody. It combines the specificity of the antibody and high efficiency of chemical drug, which has been the latest development of tumor targeted drugs. Tubulysins are a family of tetrapeptides discovered from myxobacteria which can inhibit polymerization of microtubules, and exhibit extremely high antitumor activity (IC50 ﹤1nM), thereby can be modified as the new "warhead drugs". However, natural sources of Tubulysins are limited and they are difficult to be synthesized. In our previous work, we resolved the crystal structure of Tubulysin M-tubulin complex, and revealed its mechanism of molecular pharmacology，then summarized the key structure-activity relationship of Tubulysins. Based on the information of structural biology, following the requirements of "warhead drug", our final goal of this project is to design and synthesize a series of Tubulysin derivatives, and make a study of their anti-tumor effect to screen out novel Tubulysin derivatives which show high antimor activity and stability. Then making novel Tubulysin derivatives couple with anti-HER2 mutation antibody, and to study antimor activity of these ADCs. Finally we expect to get a series of novel "warhead drugs" which have independent intellectual property rights and lay a foundation for the development of ADC drugs.