Institutional Repository of Chinese Acad Sci, High Field Magnet Lab,Hefei 230031, Anhui, Peoples R China
| Discovery of 4-Methyl-N-(44(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-y1)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding | |
Wang, Qiang1,2; Liu, Feiyang1,3 ; Wang, Beilei1,3; Zou, Fengming1,2; Qi, Ziping1,2; Chen, Cheng1,3; Yu, Kailin1,3; Hu, Chen1,3; Qi, Shuang1,2; Wang, Wenchao1,2; Hu, Zhenquan1,2; Liu, Juan1; Wang, Wei1,2; Wang, Li1,3; Liang, Qianmao1; Zhang, Shanchun2,4; Ren, Tao5; Liu, Qingsong1,2,3,5; Liu, Jing1,2
| |
| 2017-01-12 | |
| 发表期刊 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 摘要 | The discovery of a novel potent type II ABL/c-KIT dual kinase inhibitor compound. 34 (CHMFL-ABL/KIT-155), which utilized a hydrogen bond formed by NH on the kinase backbone and carbonyl oxygen of 34 as a unique hinge binding, is described. 34 potently inhibited purified ABL (IC50: 46 nM) and c-KIT kinase (IC50: 75 nM) in the biochemical assays and displayed high selectivity (S Score (1) = 0.03) at the concentration of 1 mu M among 468 kinases/mutants in KINOMEscan assay. It exhibited strong antiproliferative activities against BCR-ABL/c-KIT driven CML/GISTs cancer cell lines through blockage of the BCR-ABL/c-KIT mediated signaling pathways, arresting cell cycle progression and induction of apoptosis. 34 possessed a good oral PK property and effectively suppressed the tumor progression in the K562 (CML) and GIST-T1 (GISTs) cells mediated xenograft mouse model. The distinct hinge-binding mode of 34 provided a novel pharmacophore for expanding the chemical structure diversity for the type II kinase inhibitors discovery. |
| 文章类型 | Article |
| WOS标题词 | Science & Technology ; Life Sciences & Biomedicine |
| DOI | 10.1021/acs.jmedchem.6b01290 |
| 关键词[WOS] | STRUCTURAL MECHANISM ; TYROSINE KINASE ; BCR-ABL ; RECEPTOR ; MODE ; MET |
| 收录类别 | SCI |
| 语种 | 英语 |
| 项目资助者 | Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(U1432250) ; Joint Funds of Research on Major Science Facilities, Key Program of the National NSFC(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 ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020308) ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; National Program for Support of Topnotch Young Professionals ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; "Cross-disciplinary Collaborative Teams Program for Science, Technology, and Innovation" of Chinese Academy of Sciences ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; China "Thousand Talents Program" ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; "Hundred Talents Program" of the Chinese Academy of Sciences ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) ; National Natural Science Foundation of China(81602973) |
| WOS研究方向 | Pharmacology & Pharmacy |
| WOS类目 | Chemistry, Medicinal |
| WOS记录号 | WOS:000392035100018 |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | http://ir.hfcas.ac.cn:8080/handle/334002/32787 |
| 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.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.Hefei Cosource Med Technol Co Ltd, 358 Ganquan Rd, Hefei 230031, 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 |
| 第一作者单位 | 中科院强磁场科学中心 |
| 推荐引用方式 GB/T 7714 | Wang, Qiang,Liu, Feiyang,Wang, Beilei,et al. Discovery of 4-Methyl-N-(44(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-y1)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(1):273-289. |
| APA | Wang, Qiang.,Liu, Feiyang.,Wang, Beilei.,Zou, Fengming.,Qi, Ziping.,...&Liu, Jing.(2017).Discovery of 4-Methyl-N-(44(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-y1)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding.JOURNAL OF MEDICINAL CHEMISTRY,60(1),273-289. |
| MLA | Wang, Qiang,et al."Discovery of 4-Methyl-N-(44(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-y1)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding".JOURNAL OF MEDICINAL CHEMISTRY 60.1(2017):273-289. |
| 条目包含的文件 | 下载所有文件 | |||||
| 文件名称/大小 | 文献类型 | 版本类型 | 开放类型 | 使用许可 | ||
| Discovery of 4-Methy（3516KB） | 期刊论文 | 作者接受稿 | 开放获取 | CC BY-NC-SA | 浏览 下载 | |
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。
修改评论