Fu Gui1, Jie Jiang1, Zhixiang He1, Li Li1, Yunzhan Li1, Zhou Deng1, Yue Lu1, Xinrui Wu1, Guyue Chen1, Jingyi Su1, Siyang Song1, Yue-Ming Zhang2, Cai-Hong Yun2, Xin Huang3, Ellen Weisberg4, Jianming Zhang5,6, Xianming Deng1. 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.
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.
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.
Authors: Daigen Xu; Yong Kim; Jennifer Postelnek; Minh Diem Vu; Dong-Qing Hu; Cheng Liao; Mike Bradshaw; Jonathan Hsu; Jun Zhang; Achal Pashine; Dinesh Srinivasan; John Woods; Anita Levin; Alison O'Mahony; Timothy D Owens; Yan Lou; Ronald J Hill; Satwant Narula; Julie DeMartino; Jay S Fine Journal: J Pharmacol Exp Ther Date: 2012-01-06 Impact factor: 4.030
Authors: Adelajda Zorba; Chuong Nguyen; Yingrong Xu; Jeremy Starr; Kris Borzilleri; James Smith; Hongyao Zhu; Kathleen A Farley; WeiDong Ding; James Schiemer; Xidong Feng; Jeanne S Chang; Daniel P Uccello; Jennifer A Young; Carmen N Garcia-Irrizary; Lara Czabaniuk; Brandon Schuff; Robert Oliver; Justin Montgomery; Matthew M Hayward; Jotham Coe; Jinshan Chen; Mark Niosi; Suman Luthra; Jaymin C Shah; Ayman El-Kattan; Xiayang Qiu; Graham M West; Mark C Noe; Veerabahu Shanmugasundaram; Adam M Gilbert; Matthew F Brown; Matthew F Calabrese Journal: Proc Natl Acad Sci U S A Date: 2018-07-16 Impact factor: 11.205
Authors: John C Byrd; Richard R Furman; Steven E Coutre; Ian W Flinn; Jan A Burger; Kristie A Blum; Barbara Grant; Jeff P Sharman; Morton Coleman; William G Wierda; Jeffrey A Jones; Weiqiang Zhao; Nyla A Heerema; Amy J Johnson; Juthamas Sukbuntherng; Betty Y Chang; Fong Clow; Eric Hedrick; Joseph J Buggy; Danelle F James; Susan O'Brien Journal: N Engl J Med Date: 2013-06-19 Impact factor: 91.245
Authors: Jianming Zhang; Francisco J Adrián; Wolfgang Jahnke; Sandra W Cowan-Jacob; Allen G Li; Roxana E Iacob; Taebo Sim; John Powers; Christine Dierks; Fangxian Sun; Gui-Rong Guo; Qiang Ding; Barun Okram; Yongmun Choi; Amy Wojciechowski; Xianming Deng; Guoxun Liu; Gabriele Fendrich; André Strauss; Navratna Vajpai; Stephan Grzesiek; Tove Tuntland; Yi Liu; Badry Bursulaya; Mohammad Azam; Paul W Manley; John R Engen; George Q Daley; Markus Warmuth; Nathanael S Gray Journal: Nature Date: 2010-01-13 Impact factor: 49.962
Authors: Shruti Sharma; Natalie Galanina; Ailin Guo; Jimmy Lee; Sabah Kadri; Charles Van Slambrouck; Bradley Long; Weige Wang; Mei Ming; Larissa V Furtado; Jeremy P Segal; Wendy Stock; Girish Venkataraman; Wei-Jen Tang; Pin Lu; Yue Lynn Wang Journal: Oncotarget Date: 2016-10-18