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Covalent low\u2010MW BTK kinase inhibitors have shown impressive clinical efficacy in B\u2010cell malignancies. However, the mutant Btk<\/jats:italic>C481S<\/jats:italic><\/jats:sup> poses a major challenge in the management of B\u2010cell 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\u2010resistant Btk<\/jats:italic>C481S<\/jats:italic><\/jats:sup> mutation.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>BTK\u2010Ba\/F3, BTK(C481S)\u2010Ba\/F3 cells, and human malignant B\u2010cells JeKo\u20101, Ramos, and NALM\u20106 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\u2010mediated signalling. A tumour xenograft model with BTK\u2010Ba\/F3, Ramos and BTK(C481S)\u2010Ba\/F3 cells in Nu\/nu BALB\/c mice was used to assess in vivo efficacy of XMU\u2010MP\u20103.<\/jats:p><\/jats:sec>Key Results<\/jats:title>XMU\u2010MP\u20103 is one of a group of low MW compounds that are potent non\u2010covalent BTK inhibitors. XMU\u2010MP\u20103 inhibited both BTK and the acquired mutant BTKC481S, in vitro and in vivo. Further computational modelling, site\u2010directed mutagenesis analysis, and structure\u2013activity relationships studies indicated that XMU\u2010MP\u20103 displayed a typical Type\u2010II inhibitor binding mode.<\/jats:p><\/jats:sec>Conclusion and Implications<\/jats:title>XMU\u2010MP\u20103 directly targets the BTK signalling pathway in B\u2010cell lymphoma. These findings establish XMU\u2010MP\u20103 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\u2010cell malignancies, especially those with the acquired ibrutinib\u2010resistant C481S mutation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14809","type":"journal-article","created":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T00:34:12Z","timestamp":1564533252000},"page":"4491-4509","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A non\u2010covalent inhibitor XMU\u2010MP\u20103 overrides ibrutinib\u2010resistant Btk<\/i>C481S<\/i><\/sup><\/scp> mutation in B\u2010cell malignancies"],"prefix":"10.1111","volume":"176","author":[{"given":"Fu","family":"Gui","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State\u2010Province Joint Engineering 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