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Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC
Chen, Yongfei1,2; Wu, Jiaxin1,3; Wang, Aoli1; Qi, Ziping1,2; Jiang, Taoshan1,4; Chen, Cheng1,3; Zou, Fengming1,2; Hu, Chen1,3; Wang, Wei1,2; Wu, Hong1,2; Hu, Zhenquan1,2; Wang, Wenchao1,2; Wang, Beilei1,3; Wang, Li1,3; Ren, Tao5; Zhang, Shanchun2,6; Liu, Qingsong1,2,3,5; Liu, Jing1,2
2017-10-20
Source PublicationEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume139Issue:Pages:674-697
AbstractRecently, more and more concomitant EGFR mutations and ALK rearrangement are observed from the clinic, which still lacks effective single-agent therapy, Starting from ALK inhibitor 14 (TAE684), we have developed a highly potent EGFR/ALK dual kinase inhibitor compound 18 (CHMFL-ALK/EGFR-050), which potently inhibited EGFR L858R, del 19 and T790M mutants as well as EML4-ALK, R1275Q L1196M, F1174L and C1156Y mutants biochemically. Compound 18 significantly inhibited the proliferation of EGFR mutant and EML4-ALK driven NSCLC cell lines. In the cellular context it strongly affected EGFR and ALK mediated signaling pathways, induced apoptosis and arrested cell cycle at G0/G1 phase. In the in vivo studies, 18 significantly suppressed the tumor growth in H1975 cell inoculated xenograft model (40 mg/kg/d, TGI: 99%) and H3122 cell inoculated xenograft model (40 mg/kg/d, TGI: 78%). Compound 18 might be a potential drug candidate for EGFR- or ALK-individual as well as concomitant EGFR/ALK NSCLC. (C) 2017 Elsevier Masson SAS. All rights reserved.
SubtypeArticle
KeywordEgfr Alk Dual Kinase Inhibitor Non-small Cell Lung Cancer
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
Funding OrganizationNational Natural Science Foundation of China(U1432250 ; Chinese Academy of Sciences(XDA12020308) ; Natural Science Foundation of Anhui province(1508085MB23 ; Postdoctoral Innovative Talents Support Program(InBX201600169) ; CAS/SAFEA ; Hefei Science Center of CAS(2016HSC-IU 007) ; Presidential Foundation of Hefei Institutes of Physical Science of CAS(YZJJ201517) ; National Program for Support of Top-Notch Young Professionals ; CAS ; 21402207 ; 1608085QH180 ; 81402797) ; 1708085MH208) ; National Natural Science Foundation of China(U1432250 ; Chinese Academy of Sciences(XDA12020308) ; Natural Science Foundation of Anhui province(1508085MB23 ; Postdoctoral Innovative Talents Support Program(InBX201600169) ; CAS/SAFEA ; Hefei Science Center of CAS(2016HSC-IU 007) ; Presidential Foundation of Hefei Institutes of Physical Science of CAS(YZJJ201517) ; National Program for Support of Top-Notch Young Professionals ; CAS ; 21402207 ; 1608085QH180 ; 81402797) ; 1708085MH208)
DOI10.1016/j.ejmech.2017.08.035
WOS KeywordCELL LUNG-CANCER ; EML4-ALK FUSION GENE ; WILD-TYPE EGFR ; CLINICAL-RESPONSE ; ALK ; MUTATIONS ; GEFITINIB ; RECEPTOR ; GROWTH ; T790M
Indexed BySCI
Language英语
Funding OrganizationNational Natural Science Foundation of China(U1432250 ; Chinese Academy of Sciences(XDA12020308) ; Natural Science Foundation of Anhui province(1508085MB23 ; Postdoctoral Innovative Talents Support Program(InBX201600169) ; CAS/SAFEA ; Hefei Science Center of CAS(2016HSC-IU 007) ; Presidential Foundation of Hefei Institutes of Physical Science of CAS(YZJJ201517) ; National Program for Support of Top-Notch Young Professionals ; CAS ; 21402207 ; 1608085QH180 ; 81402797) ; 1708085MH208) ; National Natural Science Foundation of China(U1432250 ; Chinese Academy of Sciences(XDA12020308) ; Natural Science Foundation of Anhui province(1508085MB23 ; Postdoctoral Innovative Talents Support Program(InBX201600169) ; CAS/SAFEA ; Hefei Science Center of CAS(2016HSC-IU 007) ; Presidential Foundation of Hefei Institutes of Physical Science of CAS(YZJJ201517) ; National Program for Support of Top-Notch Young Professionals ; CAS ; 21402207 ; 1608085QH180 ; 81402797) ; 1708085MH208)
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000412788200052
Citation statistics
Cited Times:6[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.hfcas.ac.cn:8080/handle/334002/33792
Collection中科院强磁场科学中心
Affiliation1.Chinese Acad Sci, High Magnet Field Lab, Mailbox 1110,350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
2.CHMFL HCMTC Target Therapy Joint Lab, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
3.Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China
4.Anhui Agr Univ, Sch Life Sci, Hefei 230036, Anhui, Peoples R China
5.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China
6.Hefei Cosource Med Technol Co LTD, 358 Ganquan Rd, Hefei 230031, Anhui, Peoples R China
Recommended Citation
GB/T 7714
Chen, Yongfei,Wu, Jiaxin,Wang, Aoli,et al. Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,139(无):674-697.
APA Chen, Yongfei.,Wu, Jiaxin.,Wang, Aoli.,Qi, Ziping.,Jiang, Taoshan.,...&Liu, Jing.(2017).Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,139(无),674-697.
MLA Chen, Yongfei,et al."Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 139.无(2017):674-697.
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