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A non-covalent inhibitor XMU-MP-3 overrides ibrutinib-resistant BtkC481S mutation in B-cell malignancies.
Gui, Fu; Jiang, Jie; He, Zhixiang; Li, Li; Li, Yunzhan; Deng, Zhou; Lu, Yue; Wu, Xinrui; Chen, Guyue; Su, Jingyi; Song, Siyang; Zhang, Yue-Ming; Yun, Cai-Hong; Huang, Xin; Weisberg, Ellen; Zhang, Jianming; Deng, Xianming.
Afiliação
  • Gui F; 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.
  • Jiang J; 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.
  • He Z; 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.
  • Li L; 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.
  • Li Y; 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.
  • Deng Z; 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.
  • Lu Y; 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.
  • Wu X; 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.
  • Chen G; 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.
  • Su J; 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.
  • Song S; 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.
  • Zhang YM; 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.
  • Yun CH; 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.
  • Huang X; Division of Drug Discovery, Hongyun Biotech Co., Ltd., Nanjing, China.
  • Weisberg E; Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Zhang J; National Research Center for Translational Medicine, Shanghai State Key Laboratory of Medical Genomics, Rui-Jin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
  • Deng X; Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Br J Pharmacol ; 176(23): 4491-4509, 2019 12.
Article em En | MEDLINE | ID: mdl-31364164
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirazóis / Pirimidinas / Leucemia Linfocítica Crônica de Células B / Resistencia a Medicamentos Antineoplásicos / Inibidores de Proteínas Quinases / Tirosina Quinase da Agamaglobulinemia / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirazóis / Pirimidinas / Leucemia Linfocítica Crônica de Células B / Resistencia a Medicamentos Antineoplásicos / Inibidores de Proteínas Quinases / Tirosina Quinase da Agamaglobulinemia / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article