期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 176, 期 23, 页码 4491-4509出版社
WILEY
DOI: 10.1111/bph.14809
关键词
-
资金
- Fundamental Research Funds for the Central Universities of China [20720160064, 20720170067, 20720190101]
- NSFC MAJOR PROJECTS [81890994]
- Shanghai Municipal Education Commission - Gaofeng Clinical Medicine Grant Support
- Program of Introducing Talents of Discipline to Universities [B06016]
- China's 1000 Young Talents Program
- National Natural Science Foundation of China [81422045, 81603131, 81661138005, U1405223]
- Ministry of Science and Technology of the People's Republic of China [2016YFA0502001, 2017YFA0504504]
Background and Purpose Bruton's tyrosine kinase (BTK) plays a key role in B-cell receptor signalling by regulating cell proliferation and survival in various B-cell malignancies. Covalent low-MW BTK kinase inhibitors have shown impressive clinical efficacy in B-cell malignancies. However, the mutant Btk(C481S) poses a major challenge in the management of B-cell malignancies by disrupting the formation of the covalent bond between BTK and irreversible inhibitors, such as ibrutinib. The present studies were designed to develop novel BTK inhibitors targeting ibrutinib-resistant Btk(C481S) mutation. Experimental Approach BTK-Ba/F3, BTK(C481S)-Ba/F3 cells, and human malignant B-cells JeKo-1, Ramos, and NALM-6 were used to evaluate cellular potency of BTK inhibitors. The in vitro pharmacological efficacy and compound selectivity were assayed via cell viability, colony formation, and BTK-mediated signalling. A tumour xenograft model with BTK-Ba/F3, Ramos and BTK(C481S)-Ba/F3 cells in Nu/nu BALB/c mice was used to assess in vivo efficacy of XMU-MP-3. Key Results XMU-MP-3 is one of a group of low MW compounds that are potent non-covalent BTK inhibitors. XMU-MP-3 inhibited both BTK and the acquired mutant BTKC481S, in vitro and in vivo. Further computational modelling, site-directed mutagenesis analysis, and structure-activity relationships studies indicated that XMU-MP-3 displayed a typical Type-II inhibitor binding mode. Conclusion and Implications XMU-MP-3 directly targets the BTK signalling pathway in B-cell lymphoma. These findings establish XMU-MP-3 as a novel inhibitor of BTK, which could serve as both a tool compound and a lead for further drug development in BTK relevant B-cell malignancies, especially those with the acquired ibrutinib-resistant C481S mutation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据