肝癌是一种最常见的恶性肿瘤，严重危害人类健康，至今没有有效的药物治疗。990209是我们发现的一个具有显著抗肝癌活性的候选药物，临床前研究发现存在溶解度小、药代动力学性质不够稳定、有效剂量大的问题；初步的研究结果表明可能的作用靶点是酪氨酸激酶Src，有待于进一步确证。本课题计划：1）针对990209存在的问题进行优化，发现成药性更好的990209衍生物；2）通过酶、细胞和结构生物学的方法确证候选990209的抗肝癌作用机制；3）基于990209结构和可能的作用靶点Src进行计算机虚拟筛选，基于活性化合物与受体Src结合复合物的晶体结构进行合理的药物设计，由此发现新型先导化合物。预期目标是开辟以酪氨酸激酶Src为靶点的抗肝癌药物研究的新领域，为研发有效的抗肝癌药物奠定基础。

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and seriously harm to human health. Until to now, there is no efficient chemotherapeutic agents for patients with unresectable hepatocellular carcinoma. Compound 990209 is a candidate drug with significant anti-hepatoma activity, which was developed by us. However, during the preclinical phase, some shortcoming was exposed, including lower solubility, lower stability of pharmacokinetic properties and high effective dose. The preliminary results show that the possible target is the tyrosine kinase Src, which needed to be further confirmed. In this project, we will complete following works：1）Optimizing the 990209 in light of the existing problems to search for a better druggability 990209 derivatives; 2) Confirming the anti-hepatoma mechanism of candidate 990209 by the enzyme, cell and structural biology methods; 3) Founding the new lead compounds through the computer virtual screening based on the structure of 990209 and possible targets (Src) and through the rational drug design based on the crystal structure of the complex between active compound with the receptor Src. The expected goal is to develop a new field for the anti-hepatoma drug research with tyrosine kinase Src as a target and to establish the foundation for the development of effective anti-hepatoma drug.