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

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

  • Br J Pharmacol. 2019 Dec;176(23):4491-4509. doi: 10.1111/bph.14809.
Fu Gui 1,  Jie Jiang 1,  Zhixiang He 1,  Li Li 1,  Yunzhan Li 1,  Zhou Deng 1,  Yue Lu 1,  Xinrui Wu 1,  Guyue Chen 1,  Jingyi Su 1,  Siyang Song 1,  Yue-Ming Zhang 2,  Cai-Hong Yun 2,  Xin Huang 3,  Ellen Weisberg 4,  Jianming Zhang 5 6,  Xianming Deng 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Science, Xiamen University, Xiamen, China.
  • 2 Institute of Systems Biomedicine, Department of Biophysics and Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 3 Division of Drug Discovery, Hongyun Biotech Co., Ltd., Nanjing, China.
  • 4 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 5 National Research Center for Translational Medicine, Shanghai State Key Laboratory of Medical Genomics, Rui-Jin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
  • 6 Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
PMID: 31364164 DOI: 10.1111/bph.14809
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.

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