中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
Discovery of (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone (CHMFL-FLT3-122) as a Potent and Orally Available FLT3 Kinase Inhibitor for FLT3-ITD Positive Acute Myeloid Leukemia

文献类型:期刊论文

作者Li, Xixiang1,2; Wang, Aoli1,3; Yu, Kailin1,3; Qi, Ziping1,2; Chen, Cheng1,2; Wang, Wenchao1,2; Hu, Chen1,2; Wu, Hong1,3; Wu, Jiaxin1,3; Zhao, Zheng1,2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2015-12-24
卷号58期号:24页码:9625-9638
DOI10.1021/acs.jmedchem.5b01611
文献子类Article
英文摘要FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of the structure of PCI-32765 (ibrutinib), a BTK kinase inhibitor that was recently reported to bear FLT3 kinase activity through a structure-guided drug design approach, we have discovered compound 18 (CHMFL-FLT3-122), which displayed an IC50 of 40 nM against FLT3 kinase and achieved selectivity over BTK kinase (over 10-fold). It significantly inhibited the proliferation of FLT3-ITD positive AML cancer cell lines MV4-11 (GI(50) = 22 nM), MOLM13/14 (GI(50) = 21 nM/42 nM). More importantly, 18 demonstrated 170-fold selectivity between FLT3 kinase and c-KIT kinase (GI50 = 11 nM versus 1900 nM) in the TEL-fusion isogenic BaF3 cells indicating a potential to avoid the FLT3/c-KIT dual inhibition induced myelosuppression toxicity. In the cellular context it strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting the cell cycle into the G0/G1 phase. In the in vivo studies 18 demonstrated a good bioavailability (30%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (50 mg/kg) without exhibiting obvious toxicity. Compound 18 might be a potential drug candidate for FLT3-ITD positive AML.
WOS关键词ACUTE MYELOGENOUS LEUKEMIA ; MUTATIONS ; TARGET
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000367563100015
资助机构Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC Grant)(2015SRG-H5C022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC Grant)(2015SRG-H5C022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC Grant)(2015SRG-H5C022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC Grant)(2015SRG-H5C022) ; grant "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; China "Thousand Talents Program" of the Chinese Academy of Sciences ; China "Thousand Talents Program" of the Chinese Academy of Sciences ; China "Thousand Talents Program" of the Chinese Academy of Sciences ; China "Thousand 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 ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC Grant)(2015SRG-H5C022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC Grant)(2015SRG-H5C022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC Grant)(2015SRG-H5C022) ; Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC Grant)(2015SRG-H5C022) ; grant "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; grant "Cross-Disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; Anhui Province Natural Science Foundation Annual Key Program(1301023011) ; China "Thousand Talents Program" of the Chinese Academy of Sciences ; China "Thousand Talents Program" of the Chinese Academy of Sciences ; China "Thousand Talents Program" of the Chinese Academy of Sciences ; China "Thousand 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
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/22224]  
专题合肥物质科学研究院_中科院强磁场科学中心
作者单位1.Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China
2.CHMFL HCMTC Target Therapy Joint Lab, Hefei 230031, Anhui, Peoples R China
3.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China
4.Hefei Cosource Med Technol Co Ltd, Hefei 230031, Anhui, Peoples R China
5.Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China
推荐引用方式
GB/T 7714
Li, Xixiang,Wang, Aoli,Yu, Kailin,et al. Discovery of (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone (CHMFL-FLT3-122) as a Potent and Orally Available FLT3 Kinase Inhibitor for FLT3-ITD Positive Acute Myeloid Leukemia[J]. JOURNAL OF MEDICINAL CHEMISTRY,2015,58(24):9625-9638.
APA Li, Xixiang.,Wang, Aoli.,Yu, Kailin.,Qi, Ziping.,Chen, Cheng.,...&Liu, Qingsong.(2015).Discovery of (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone (CHMFL-FLT3-122) as a Potent and Orally Available FLT3 Kinase Inhibitor for FLT3-ITD Positive Acute Myeloid Leukemia.JOURNAL OF MEDICINAL CHEMISTRY,58(24),9625-9638.
MLA Li, Xixiang,et al."Discovery of (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone (CHMFL-FLT3-122) as a Potent and Orally Available FLT3 Kinase Inhibitor for FLT3-ITD Positive Acute Myeloid Leukemia".JOURNAL OF MEDICINAL CHEMISTRY 58.24(2015):9625-9638.

入库方式: OAI收割

来源:合肥物质科学研究院

浏览0
下载0
收藏0
其他版本

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。