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Discovery of 4-((N-(2-(dimethylamino)ethyl)acrylamido)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (CHMFL-PDGFR-159) as a highly selective type II PDGFR alpha kinase inhibitor for PDGFR alpha driving chronic eosinophilic leukemia
Wang, Qiang1,2; Liu, Feiyang1,3; Qi, Shuang1,2; Qi, Ziping1,2; Yan, Xiao-E.4; Wang, Beilei1,3; Wang, Aoli1,3; Wang, Wei1,2; Chen, Cheng1,3; Liu, Xiaochuan1,2; Jiang, Zongru1,3; Hu, Zhenquan1,2; Wang, Li1,3; Wang, Wenchao1,2; Ren, Tao5; Zhang, Shanchun2,6; Yun, Cai-Hong4; Liu, Qingsong1,2,3,7; Liu, Jing1,2,7
2018-04-25
Source PublicationEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN0223-5234
Volume150Issue:Pages:366-384
Abstract

Through exploration of the non-highly conserved allosteric hydrophobic pocket generated by DFG-out shifting in the inactive conformation, we discovered a highly selective type II PDGFR alpha kinase inhibitor 15i (CHMFL-PDGFR alpha-159), which exhibited strong potency against purified PDGFR alpha (IC50: 132 nM) but not structurally similar PDGFR beta, ABL, c-KIT and VEGFR2 kinases. In addition, it displayed a high selectivity profile (S score (10) = 0.02) at the concentration of 1 mu M among 468 kinases/mutants in the KINOMEscan profiling. X-ray crystal structure of 15i in complex with PDGFR? revealed a distinct binding feature in the allosteric hydrophobic pocket which might help to expand the diversity of type II kinase inhibitors. Compound 15i potently inhibited the proliferation of PDGFR alpha driving Chronic Eosinophilic Leukemia (CEL) cell line EOL-1 through strong blockage of PDGFR alpha mediated signaling pathways, arresting cell cycle progression, and induction of apoptosis. Furthermore, compound 15i effectively suppressed the EOL-1 tumor progression in the xenograft model and increased the survival rate in the engraftment tumor model. (C) 2018 Elsevier Masson SAS. All rights reserved.

KeywordPDGFR kinase Type II inhibitor Kinase inhibitor CEL
DOI10.1016/j.ejmech.2018.03.003
WOS KeywordRECEPTOR TYROSINE KINASE ; GASTROINTESTINAL STROMAL TUMORS ; GROWTH-FACTOR ; C-KIT ; MODEL ; RESISTANCE ; IMATINIB ; MECHANISM ; DISEASE ; MUSCLE
Indexed BySCI
Language英语
Funding ProjectHundred Talents Program of CAS ; National Program for Support of Top-Notch Young Professionals ; Science and Technology Projects of Anhui Province[16030801114] ; Science and Technology Projects of Anhui Province[1704a0802140] ; Science and Technology Projects of Anhui Province[1501041175] ; Natural Science Foundation of Anhui Province[1608085QH180] ; Natural Science Foundation of Anhui Province[1708085QH197] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020351] ; National Natural Science Foundation of China[31270769] ; National Natural Science Foundation of China[81602973] ; Natural Science Foundation of Anhui Province[1708085MH208] ; National Natural Science Foundation of China[U1532154] ; National Natural Science Foundation of China[U1432250] ; National Natural Science Foundation of China[U1432250] ; National Natural Science Foundation of China[U1532154] ; Natural Science Foundation of Anhui Province[1708085MH208] ; National Natural Science Foundation of China[81602973] ; National Natural Science Foundation of China[31270769] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020351] ; Natural Science Foundation of Anhui Province[1708085QH197] ; Natural Science Foundation of Anhui Province[1608085QH180] ; Science and Technology Projects of Anhui Province[1501041175] ; Science and Technology Projects of Anhui Province[1704a0802140] ; Science and Technology Projects of Anhui Province[16030801114] ; National Program for Support of Top-Notch Young Professionals ; Hundred Talents Program of CAS
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000430891400026
PublisherELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
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/334002/35478
Collection中科院强磁场科学中心
Corresponding AuthorYun, Cai-Hong; Liu, Qingsong; Liu, Jing
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 230036, Anhui, Peoples R China
4.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Inst Syst Biomed,Dept Biophys, Beijing 100191, 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
7.Chinese Acad Sci, Hefei Sci Ctr, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
Recommended Citation
GB/T 7714
Wang, Qiang,Liu, Feiyang,Qi, Shuang,et al. Discovery of 4-((N-(2-(dimethylamino)ethyl)acrylamido)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (CHMFL-PDGFR-159) as a highly selective type II PDGFR alpha kinase inhibitor for PDGFR alpha driving chronic eosinophilic leukemia[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,150(无):366-384.
APA Wang, Qiang.,Liu, Feiyang.,Qi, Shuang.,Qi, Ziping.,Yan, Xiao-E..,...&Liu, Jing.(2018).Discovery of 4-((N-(2-(dimethylamino)ethyl)acrylamido)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (CHMFL-PDGFR-159) as a highly selective type II PDGFR alpha kinase inhibitor for PDGFR alpha driving chronic eosinophilic leukemia.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,150(无),366-384.
MLA Wang, Qiang,et al."Discovery of 4-((N-(2-(dimethylamino)ethyl)acrylamido)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (CHMFL-PDGFR-159) as a highly selective type II PDGFR alpha kinase inhibitor for PDGFR alpha driving chronic eosinophilic leukemia".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 150.无(2018):366-384.
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