针对B细胞淋巴瘤的激酶抑制剂的发现和药物学研究

发布时间：2018-03-24 06:11

本文选题：BTK　切入点：不可逆抑制剂　出处：《中国科学技术大学》2017年硕士论文

【摘要】：BTK(Bruton' s tyrosine kinase)是一个从属于TEC激酶家族的非受体酪氨酸激酶,主要在B细胞中表达,广泛分布于淋巴系统、造血系统和血液系统中,在BCR信号通路中起重要作用。有研究表明BTK的异常表达与B细胞淋巴瘤有密切关系。虽然近年来已经有一些BTK抑制剂在进行临床前或临床研究,但是大部分抑制剂并不仅仅抑制BTK,即靶向了如BMX、JAK3或EGFR等其它与BTK结构相似的激酶。而对这些激酶的抑制作用在临床上容易对病人造成如恶心、呕吐等不良反应。通过基于结构的药物设计方法,我们发现了高活性(IC50:7nM)的不可逆的BTK抑制剂CHMFL-BTK-01(化合物9),并且在468种激酶(包括突变型)活性检测中,表现出极好的选择性。该抑制剂完全没有显示出靶向BMX、JAK3和EGFR这些与BTK结构相似的激酶的活性。在X射线晶体结构和半胱氨酸-丝氨酸突变的实验中也证实了CHMFL-BTK-01的结合模式是不可逆的。CHMFL-BTK-01不仅抑制了BTK Y223的自磷酸化(EC50:30nM),还将U2932和Pfeiffer细胞阻滞在G0/G1期,并且诱导细胞凋亡。本论文主要从如下两个方面进行研究:1.靶向BTK的高选择性的不可逆抑制剂CHMFL-BTK-01(化合物9)的发现2.CHMFL-BTK-01(化合物9)的药理学及药代动力学研究通过上述方面的研究,我们认为CHMFL-BTK-01是一个很好的用来研究BTK介导的信号通路以及作用的药物学工具小分子。
[Abstract]:BTK Bruton's tyrosine kinase is a non-receptor tyrosine kinase belonging to the TEC kinase family. It is expressed mainly in B cells and widely distributed in the lymphatic system, hematopoietic system and blood system. It has been shown that abnormal expression of BTK is closely related to B-cell lymphoma. Although in recent years, there have been some BTK inhibitors in pre-clinical or clinical studies. But most inhibitors don't just inhibit BTKs, that is, they target other kinases similar to the structure of BTK, such as BMXG JAK3 or EGFR. The inhibition of these kinases is likely to cause nausea in patients clinically. Adverse reactions such as vomiting. Through a structure-based drug design approach, we found an irreversible BTK inhibitor CHMFL-BTK-01 (compound 9N) with a high activity of IC50: 7nMand detected the activity of 468 kinases (including mutant). The inhibitor showed no activity in targeting BMXG JAK3 and EGFR, which are structurally similar to BTK. In X-ray crystal structure and cysteine-serine mutation experiments, CHMFL-BTK-01 's structure was also confirmed. The binding pattern was irreversible. CHMFL-BTK-01 not only inhibited the autophosphorylation of BTK Y223, EC50: 30nMN, but also blocked U2932 and Pfeiffer cells in G0/G1 phase. In this thesis, we mainly studied the following two aspects: 1.The discovery of CHMFL-BTK-01 (compound 9), a highly selective irreversible inhibitor of BTK. 2. Pharmacological and pharmacokinetic studies of CHMFL-BTK-01 (compound 9). We believe that CHMFL-BTK-01 is a good pharmacological tool for the study of BTK mediated signaling pathways as well as pharmacological tools.
【学位授予单位】：中国科学技术大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R979.1

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