Institutional Repository of Chinese Acad Sci, High Field Magnet Lab,Hefei 230031, Anhui, Peoples R China
Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia | |
Liang, Xiaofei1,2; Wang, Beilei1,3; Chen, Cheng1,3; Wang, Aoli1,2; Hu, Chen1,3; Zou, Fengming1,2; Yu, Kailin1,2; Liu, Qingwang2,4; Li, Feng1,3; Hu, Zhenquan1,2; Lu, Tingting1,3; Wang, Junjie1,3; Wang, Li1,3; Weisberg, Ellen L.5; Li, Lili6; Xia, Ruixiang6; Wang, Wenchao1,2; Ren, Tao2,4; Ge, Jian6; Liu, Jing1,2,4; Liu, Qinsong1,2,3,4,7 | |
2019-01-24 | |
发表期刊 | JOURNAL OF MEDICINAL CHEMISTRY |
ISSN | 0022-2623 |
摘要 | Most of the current FMS-like tyrosine kinase 3 (FLT3) inhibitors lack selectivity between FLT3 kinase and cKIT kinase as well as the FLT3 wt and internal tandem duplication (ITD) mutants. We report a new compound 27, which displays GI(50) values of 30-80 nM against different ITD mutants and achieves selectivity over both FLT3 wt (8-fold) and cKIT kinase in the transformed BaF3 cells (>300-fold). 27 potently inhibits the proliferation of the FLT3-ITD-positive acute myeloid leukemia cancer lines through suppression of the phosphorylation of FLT3 kinase and downstream signaling pathways, induction of apoptosis, and arresting the cell cycle into the G0/G1 phase. 27 also displays potent antiproliferative effect against FLT3-ITD-positive patient primary cells, whereas it does not apparently affect FLT3 wt primary cells. In addition, it also exhibits a good therapeutic window to PBMC compared to PKC412. In the in vivo studies, 27 demonstrates favorable PK profiles and suppresses the tumor growth in the MV4-11 cell inoculated mouse xenograft model. |
DOI | 10.1021/acs.jmedchem.8b01594 |
关键词[WOS] | RAF/MEK/ERK PATHWAY ; RATIONAL DESIGN ; MUTATIONS ; IDENTIFICATION ; CRENOLANIB ; SORAFENIB ; TARGETS ; CANCER ; CELLS |
收录类别 | SCI |
语种 | 英语 |
资助项目 | National Natural Science Foundation of China[81773777] ; National Natural Science Foundation of China[81673469] ; National Natural Science Foundation of China[81872748] ; National Natural Science Foundation of China[81872745] ; National Natural Science Foundation of China[81803366] ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020211] ; Natural Science Foundation of Anhui Province[1808085MH268] ; Science and Technology Major Projects of Anhui Province[16030801114] ; Science and Technology Major Projects of Anhui Province[17030801025] ; China Post-doctoral Science Foundation[2018T110634] ; China Post-doctoral Science Foundation[2018M630720] ; Frontier Science Key Research Program of CAS[QYZDB-SSW-SLH037] ; Youth Innovation Promotion Association of CAS[2016385] ; Hefei leading talent |
项目资助者 | National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Personalized Medicines Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; Science and Technology Major Projects of Anhui Province ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; China Post-doctoral Science Foundation ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Youth Innovation Promotion Association of CAS ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent ; Hefei leading talent |
WOS研究方向 | Pharmacology & Pharmacy |
WOS类目 | Chemistry, Medicinal |
WOS记录号 | WOS:000457067600030 |
出版者 | AMER CHEMICAL SOC |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://ir.hfcas.ac.cn:8080/handle/334002/41689 |
专题 | 中科院强磁场科学中心 |
通讯作者 | Ge, Jian; Liu, Jing; Liu, Qinsong |
作者单位 | 1.Chinese Acad Sci, Hefei Inst Phys Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China 2.Precis Med Res Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China 3.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China 4.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China 5.Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA 6.Anhui Med Univ, Dept Hematol, Affiliated Hosp 1, Hefei 230022, Anhui, Peoples R China 7.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei 230601, Anhui, Peoples R China |
推荐引用方式 GB/T 7714 | Liang, Xiaofei,Wang, Beilei,Chen, Cheng,et al. Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(2):875-892. |
APA | Liang, Xiaofei.,Wang, Beilei.,Chen, Cheng.,Wang, Aoli.,Hu, Chen.,...&Liu, Qinsong.(2019).Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia.JOURNAL OF MEDICINAL CHEMISTRY,62(2),875-892. |
MLA | Liang, Xiaofei,et al."Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia".JOURNAL OF MEDICINAL CHEMISTRY 62.2(2019):875-892. |
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 N-(4-(6(13868KB) | 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