Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode

doi:10.1021/acs.jmedchem.6b01907

HFCAS OpenIR > 中科院强磁场科学中心

	Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode
	Wang, Aoli1,2 ; Li, Xixiang1,3 ; Wu, Hong1,3 ; Zou, Fengming 1,3; Yan, Xiao-E 4,5; Chen, Cheng 1,2; Hu, Chen1,2 ; Yu, Kailin 1,2; Wang, Wenchao1,3 ; Zhao, Peng 4,5; Wu, Jiaxin 1,2; Qi, Ziping 1,3; Wang, Wei1,3 ; Wang, Beilei 1,2; Wang, Li 1,2; Ren, Tao 6; Zhang, Shanchun 3,7; Yun, Cai-Hong 4,5; Liu, Jing 1,3; Liu, Qingsong1,2,3,6
	2017-04-13
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY
摘要	On the basis of Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-helix-out" inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC.
文章类型	Article
WOS标题词	Science & Technology ; Life Sciences & Biomedicine
DOI	10.1021/acs.jmedchem.6b01907
关键词[WOS]	CELL LUNG-CANCER ; T790M MUTATION ; RESISTANCE ; SYSTEM ; CRYSTALLOGRAPHY ; GEFITINIB ; SOFTWARE ; BIOLOGY ; POTENT ; L858R
收录类别	SCI
语种	英语
项目资助者	National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; National Natural Science Foundation of China(U1432250 ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; CAS/SAFEA International Partnership Program for Creative Research Teams ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Cross disciplinary Collaborative Teams Program for Science, Technology and Innovation of CAS ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; Hefei Science Center of CAS(2016HSC-IU 007) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Key Research and Development Program of China(2016YFA0400900) ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; National Program for Support of Top-notch Young Professionals ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; Chinese Academy of Sciences ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; China Postdoctoral Science Foundation(BX201600169) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769) ; 31270769)
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000399436100022
引用统计	被引频次：22[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/334002/33341
专题	中科院强磁场科学中心
作者单位	1.Chinese Acad Sci, High Magnet Field Lab, Mailbox 1110,350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China 2.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China 3.CIIMFL HCMTC Target Therapy Joint Lab, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China 4.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biophys, Beijing 100191, Peoples R China 5.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Inst Syst Biomed, Beijing 100191, Peoples R China 6.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China 7.Hefei Cosource Med Technol Co Ltd, 358 Ganquan Rd, Hefei 230031, Anhui, Peoples R China
推荐引用方式 GB/T 7714	Wang, Aoli,Li, Xixiang,Wu, Hong,et al. Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(7):2944-2962.
APA	Wang, Aoli.,Li, Xixiang.,Wu, Hong.,Zou, Fengming.,Yan, Xiao-E.,...&Liu, Qingsong.(2017).Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode.JOURNAL OF MEDICINAL CHEMISTRY,60(7),2944-2962.
MLA	Wang, Aoli,et al."Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode".JOURNAL OF MEDICINAL CHEMISTRY 60.7(2017):2944-2962.