Premium
A non‐covalent inhibitor XMU‐MP‐3 overrides ibrutinib‐resistant Btk C481S mutation in B‐cell malignancies
Author(s) -
Gui Fu,
Jiang Jie,
He Zhixiang,
Li Li,
Li Yunzhan,
Deng Zhou,
Lu Yue,
Wu Xinrui,
Chen Guyue,
Su Jingyi,
Song Siyang,
Zhang YueMing,
Yun CaiHong,
Huang Xin,
Weisberg Ellen,
Zhang Jianming,
Deng Xianming
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14809
Subject(s) - bruton's tyrosine kinase , ibrutinib , b cell , chemistry , tyrosine kinase , cancer research , pharmacology , microbiology and biotechnology , biochemistry , biology , signal transduction , chronic lymphocytic leukemia , immunology , antibody , leukemia
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.