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A non-covalent inhibitor XMU-MP-3 overrides ibrutinib-resistant BtkC481S mutation in B-cell malignancies.


ABSTRACT: 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 BtkC481S 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 BtkC481S 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.

SUBMITTER: Gui F 

PROVIDER: S-EPMC6932946 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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A non-covalent inhibitor XMU-MP-3 overrides ibrutinib-resistant Btk<sup>C481S</sup> mutation in B-cell malignancies.

Gui Fu F   Jiang Jie J   He Zhixiang Z   Li Li L   Li Yunzhan Y   Deng Zhou Z   Lu Yue Y   Wu Xinrui X   Chen Guyue G   Su Jingyi J   Song Siyang S   Zhang Yue-Ming YM   Yun Cai-Hong CH   Huang Xin X   Weisberg Ellen E   Zhang Jianming J   Deng Xianming X  

British journal of pharmacology 20191209 23


<h4>Background and purpose</h4>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<sup>C481S</sup> 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 ibrutini  ...[more]

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