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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
Source PublicationEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume137Pages:545-557
AbstractThrough 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.
SubtypeArticle
KeywordBtk Kinase Inhibitor Irreversible Inhibitor Structure-activity Relationship B-cell Lymphoma
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
Funding OrganizationNational 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
WOS KeywordX-LINKED AGAMMAGLOBULINEMIA ; DISCOVERY ; GENE ; EXPRESSION ; LYMPHOMA ; LEUKEMIA ; MUTANT ; CELLS
Indexed BySCI
Language英语
Funding OrganizationNational 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 Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000407412200035
Citation statistics
Cited Times:4[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.hfcas.ac.cn:8080/handle/334002/33629
Collection中科院强磁场科学中心
Affiliation1.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
Recommended Citation
GB/T 7714
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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