Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mutants in FLT3-ITD Positive AML
文献类型：期刊论文
| 作者 | Wang, Aoli1,2 ; Li, Xixiang1,2; Chen, Cheng1,3; Wu, Hong1,2; Qi, Ziping1,2; Hu, Chen1,3; Yu, Kailin1,3; Wu, Jiaxin1,3; Liu, Juan4; Liu, Xiaochuan1,2
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2017-10-26 |
| 卷号 | 60期号:20页码:8407-8424 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.7b00840 |
| 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 our previous study that ibrutinib (9) exhibited selective and moderate inhibitory activity against FLT3-ITD positive AML cells, through a structure-guided drug design approach, we have discovered a new type II FLT3 kinase inhibitor, compound 14 (CHMFL-FLT3-213), which exhibited highly potent inhibitory effects against FLT3TTD mutant and associated oncogenic mutations (including FLT3-D835Y/H/V, FLT3-ITD-D835Y/I/N/A/G/Del, and FLT3-ITD-F691L). In the cellular context 14 strongly affected FLT3-TTD mediated signaling pathways and induced apoptosis by arresting cell cycle into G0/G1 phase. In the in vivo studies 14 demonstrated an acceptable bioavaOability (F = 19%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (15 mg kg(-1) day(-1), TGI = 97%) without exhibiting obvious toxicity. Compound 14 might be a potential drug candidate for FLT3-TTD positive AML. |
| WOS关键词 | ACUTE MYELOID-LEUKEMIA ; IBRUTINIB ; RESISTANCE ; MUTATION ; CELLS |
| 资助项目 | National Natural Science Foundation of China[U1432250] ; National Natural Science Foundation of China[81471773] ; National Natural Science Foundation of China[81473088] ; National Natural Science Foundation of China[U1532154] ; National Key Research and Development Program of China[2016YFA0400900] ; Natural Science Foundation of Anhui Province[1708085MH208] ; Natural Science Foundation of Anhui Province[1608085QH180] ; Hundred Talents Program of CAS ; Personalized Medicines-Molecular Signature-Based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020308] ; Postdoctoral Innovative Talents Support Program[BX201600169] ; CAS/SAFEA International Partnership Program |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000414114300012 |
| 源URL | [http://ir.hfcas.ac.cn:8080/handle/334002/35656]  |
| 专题 | 合肥物质科学研究院_中科院强磁场科学中心 |
| 通讯作者 | Xia, Ruixiang; Liu, Jing; Liu, Qingsong |
| 作者单位 | 1.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.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China 5.Anhui Med Univ, Affiliated Hosp 1, Dept Hematol, Hefei 230022, Anhui, Peoples R China 6.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,Chen, Cheng,et al. Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mutants in FLT3-ITD Positive AML[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(20):8407-8424. |
| APA | Wang, Aoli.,Li, Xixiang.,Chen, Cheng.,Wu, Hong.,Qi, Ziping.,...&Liu, Qingsong.(2017).Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mutants in FLT3-ITD Positive AML.JOURNAL OF MEDICINAL CHEMISTRY,60(20),8407-8424. |
| MLA | Wang, Aoli,et al."Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mutants in FLT3-ITD Positive AML".JOURNAL OF MEDICINAL CHEMISTRY 60.20(2017):8407-8424. |
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来源：合肥物质科学研究院
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