淋巴瘤是全球发病率增长速度最快的恶性肿瘤之一。在多种B细胞淋巴瘤中，BCR信号通路通常过度活跃，通过抑制BCR信号转导，可抑制恶性B细胞的增殖、存活。Syk是BCR信号通路中的一个关键性激酶，被认为是治疗各种血液系统癌症等疾病的潜在靶点。虽然目前已有多个Syk 抑制剂进入不同的临床研究阶段，但由于其选择性不佳而造成脱靶性毒性，给临床开发带来很大的安全性问题，开发有效且安全的Syk抑制剂是目前所面临的迫切问题。前期我们获得了一个有着良好选择性和高活性的新型化合物II-6，但代谢不够稳定。本项目将以化合物II-6为先导物，结合合理的药物设计，对先导物的结构进行优化，进一步提高选择性，改善成药性，同时深入研究该类化合物的细胞作用机制，为靶向Syk的抗肿瘤药物的研发提供理论和物质基础。希望通过本研究发现更具潜力和安全性的新型选择性Syk抑制剂，最终获得具有自主知识产权的抗肿瘤临床候选化合物。

Lymphoma is one of the most fast growing malignant tumors worldwide. Among multiple types of B cell lymphomas, BCR signal pathway is usually over-activated. Thus, inhibition of BCR signal transduction pathway may suppress the proliferation and survival of malignant B cells. Syk is a critical kinase discovered in BCR signal pathway and is generally acknowledged as a potential target for blood cancer treatment. Although mutiple Syk inhibitors have entered in clinical study of different phases, their off-target toxicity causes significant safety issues for clinical drug development due to the lack of selectivity. Thus, the development of effective and safe Syk inhibitors is an urgent problem. In the previous study, we have obtained a novel Syk inhibitor II-6 of good selectivity with in vitro potent inhibitory activity. Based on the lead compound II-6, this project aims to improve further the selectivity and drug-likeness using rational drug design strategies and further investigate the cellular mechanism of action for this type of compounds in the BCR signaling pathway, which provide theoretical and material foundation for Syk-targeted antitumor drug discovery. Through this program, we hope to discover novel Syk inhibitors with greater safety and potentiality, and finally obtain antitumor clinical candidates with independent intellectual property rights.