A non-covalent inhibitor XMU-MP-3 overrides ibrutinib-resistant Btk
| Autor: | Fu, Gui, Jie, Jiang, Zhixiang, He, Li, Li, Yunzhan, Li, Zhou, Deng, Yue, Lu, Xinrui, Wu, Guyue, Chen, Jingyi, Su, Siyang, Song, Yue-Ming, Zhang, Cai-Hong, Yun, Xin, Huang, Ellen, Weisberg, Jianming, Zhang, Xianming, Deng |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Cell Survival Mice Nude Antineoplastic Agents Mice Structure-Activity Relationship Piperidines Agammaglobulinaemia Tyrosine Kinase Animals Humans Protein Kinase Inhibitors Letter to the Editor Cells Cultured Cell Proliferation Mice Inbred BALB C Dose-Response Relationship Drug Molecular Structure Adenine Neoplasms Experimental Leukemia Lymphocytic Chronic B-Cell Molecular Docking Simulation HEK293 Cells Pyrimidines Drug Resistance Neoplasm Pyrazoles Female Drug Screening Assays Antitumor Signal Transduction |
| Zdroj: | Br J Pharmacol |
| ISSN: | 1476-5381 |
| Popis: | 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 BtkBTK-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.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.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. |
| Databáze: | OpenAIRE |
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