海南水锦树属植物中BTK抑制剂的发现及其基于BCR信号通路抑制的抗MCL作用机制研究

套细胞淋巴瘤(MCL)是一种罕见的起病隐匿、侵袭性强、易复发、预后差的成熟B细胞恶性肿瘤。目前临床上尚没有根治MCL的有效药物和治疗方案，MCL被认为是一种难以治愈的疾病。近来，Bruton’s酪氨酸激酶(BTK)抑制剂类药物在MCL治疗上获得了突破性进展，已成为当前抗MCL药物研发的热点。在前期研究中我们发现海南水锦树的总生物碱提取物具有显著的抗MCL活性和BTK抑制活性，进而在活性评价结果的指导下对该提取物的化学成分进行了初步研究，发现了系列结构新颖、抗MCL活性和BTK抑制活性显著的生物碱，基于这些，本项目拟对海南水锦树属植物中的生物碱进行系统研究，进而对分离得到的生物碱的抗MCL活性和BTK抑制活性进行评价，寻找并发现活性显著的生物碱，总结构效关系，并开展活性化合物基于BCR信号通路抑制的作用机制研究，为结构新颖、机制独特、副作用少的BTK抑制剂类抗MCL新药的开发提供科学依据。

Mantle cell lymphoma (MCL) is a rare, insidious and aggressive mature B cell malignancy that is prone to relapse and has a poor prognosis. Currently, there is no effective drugs and treatment options for the cure of MCL in clinical practice, which is considered to be a disease that is difficult to cure. Recently, Bruton’s tyrosine kinase (BTK) inhibitors have achieved a breakthrough in the treatment of MCL and have become the hotspot of research and development of anti-MCL drugs. In our preliminary investigation, we found that the total alkaloid extract from the stems and leaves of Wendlandia merrilliana displayed significant anti-MCL activity and remarkable inhibitory activity on BTK in vitro. Under the guidance of the results of activity evaluation experiments, a preliminary phytochemical study on the total alkaloid extract from the stems and leaves of W. merrilliana was thus implemented and had resulted in the isolation and identification of a series of novel alkaloids with significant anti-MCL activities as well as remarkable inhibitory activities on BTK. Based on the above those findings, this project intends to carry out a systematic study on the alkaloids from the plants belonging to the genus Wendlandia distributed in Hainan Island. In addition, the anti-MCL activities, the inhibitory activities on BTK and the structure-activity relationships of these isolated alkaloids from the plants belonging to the genus Wendlandia distributed in Hainan Island will be evaluated and summarized. Furthermore, the mechanisms of action based on the inhibitory effects against the BCR signaling pathway of the alkaloids with significant anti-MCL activities as well as remarkable inhibitory activities on BTK will be also explored. The findings of this project could provide scientific evidence for the research and development of new BTK inhibitors used as anti-MCL drugs with novel chemical structures, unique mechanisms of action as well as less toxic and side effects.