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Structure-activity relationship investigation for benzonaphthyridinone derivatives as novel potent Bruton's tyrosine kinase (BTK) irreversible inhibitors
Wang, Beilei1,2; Deng, Yuanxin1,2; Chen, Yongfei1; Yu, Kailin1,2; Wang, Aoli1,2; Liang, Qianmao1; Wang, Wei1,3; Chen, Cheng1,2; Wu, Hong1,3; Hu, Chen1,2; Miao, Weili4; Hur, Wooyoung5; Wang, Wenchao1,2; Hu, Zhenquan1,3; Weisberg, Ellen L.5; Wang, Jinhua6; Ren, Tao7; Wang, Yinsheng4; Gray, Nathanael S.6; Liu, Qingsong1,2,3,7,8; Liu, Jing1,3
2017-09-08
发表期刊EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷号137页码:545-557
摘要Through a structure-based drug design approach, a tricyclic benzonaphthyridinone pharmacophore was used as a starting point for carrying out detailed medicinal structure-activity relationhip (SAR) studies geared toward characterization of a panel of proposed BTK inhibitors, including 6 (QL-X-138), 7 (BMX-IN-1) and 8 (QL47). These studies led to the discovery of the novel potent irreversible BTK inhibitor, compound 18 (CHMFL-BTK-11). Kinetic analysis of compound 18 revealed an irreversible binding efficacy (k(inact)/K-i) of 0.01 mu M(-1)s(-1). Compound 18 potently inhibited BTK kinase Y223 auto-phosphorylation (EC50 < 100 nM), arrested cell cycle in G0/G1 phase, and induced apoptosis in Ramos, MOLM13 and Pfeiffer cells. We believe these features would make 18 a good pharmacological tool for studying BTK-related pathologies. (C) 2017 Elsevier Masson SAS. All rights reserved.
文章类型Article
关键词Btk Kinase Inhibitor Irreversible Inhibitor Structure-activity Relationship B-cell Lymphoma
WOS标题词Science & Technology ; Life Sciences & Biomedicine
资助者National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; Natural Science Foundation of Anhui province(1508085MB23) ; Natural Science Foundation of Anhui province(1508085MB23) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; CAS-SAFEA International Partnership Program for Creative Research Teams ; CAS-SAFEA International Partnership Program for Creative Research Teams ; Hefei Science Center of CAS(2016HSC-IU007) ; Hefei Science Center of CAS(2016HSC-IU007) ; U1532154 ; U1532154 ; 21402207) ; 21402207) ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; Natural Science Foundation of Anhui province(1508085MB23) ; Natural Science Foundation of Anhui province(1508085MB23) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; CAS-SAFEA International Partnership Program for Creative Research Teams ; CAS-SAFEA International Partnership Program for Creative Research Teams ; Hefei Science Center of CAS(2016HSC-IU007) ; Hefei Science Center of CAS(2016HSC-IU007) ; U1532154 ; U1532154 ; 21402207) ; 21402207)
DOI10.1016/j.ejmech.2017.06.016
关键词[WOS]X-LINKED AGAMMAGLOBULINEMIA ; DISCOVERY ; GENE ; EXPRESSION ; LYMPHOMA ; LEUKEMIA ; MUTANT ; CELLS
收录类别SCI
语种英语
资助者National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; Natural Science Foundation of Anhui province(1508085MB23) ; Natural Science Foundation of Anhui province(1508085MB23) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; CAS-SAFEA International Partnership Program for Creative Research Teams ; CAS-SAFEA International Partnership Program for Creative Research Teams ; Hefei Science Center of CAS(2016HSC-IU007) ; Hefei Science Center of CAS(2016HSC-IU007) ; U1532154 ; U1532154 ; 21402207) ; 21402207) ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; Natural Science Foundation of Anhui province(1508085MB23) ; Natural Science Foundation of Anhui province(1508085MB23) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; CAS-SAFEA International Partnership Program for Creative Research Teams ; CAS-SAFEA International Partnership Program for Creative Research Teams ; Hefei Science Center of CAS(2016HSC-IU007) ; Hefei Science Center of CAS(2016HSC-IU007) ; U1532154 ; U1532154 ; 21402207) ; 21402207)
WOS研究方向Pharmacology & Pharmacy
WOS类目Chemistry, Medicinal
WOS记录号WOS:000407412200035
引用统计
被引频次:4[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.hfcas.ac.cn:8080/handle/334002/33629
专题中科院强磁场科学中心
作者单位1.Chinese Acad Sci, High Field Magnet Lab, Mailbox 1110,350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
2.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China
3.CHMFL HCMTC Target Therapy Joint Lab, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
4.Univ Calif Riverside, Dept Chem, 900 Univ Ave, Riverside, CA 92521 USA
5.Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA
6.Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, 250 Longwood Ave,SGM 628, Boston, MA 02115 USA
7.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China
8.Chinese Acad Sci, Hefei Sci Ctr, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
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Wang, Beilei,Deng, Yuanxin,Chen, Yongfei,et al. Structure-activity relationship investigation for benzonaphthyridinone derivatives as novel potent Bruton's tyrosine kinase (BTK) irreversible inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,137:545-557.
APA Wang, Beilei.,Deng, Yuanxin.,Chen, Yongfei.,Yu, Kailin.,Wang, Aoli.,...&Liu, Jing.(2017).Structure-activity relationship investigation for benzonaphthyridinone derivatives as novel potent Bruton's tyrosine kinase (BTK) irreversible inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,137,545-557.
MLA Wang, Beilei,et al."Structure-activity relationship investigation for benzonaphthyridinone derivatives as novel potent Bruton's tyrosine kinase (BTK) irreversible inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 137(2017):545-557.
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