Design, synthesis, and evaluation of pyrido.[3,4-b]pyrazin-2(1H)-one derivatives as potent FLT3 inhibitors
文献类型：期刊论文
| 作者 | Sun, Mei4; Wang, Chang3; Wang, Peipei2; Ye, Qingqing4; Zhou, Yubo1,3 ; Li, Jia1,2,3; Liu, Tao4
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2023-02-01 |
| 卷号 | 79页码:117155 |
| 关键词 | FLT3 FLT3-D835Y Acute myeloid leukemia Structure -activity relationships |
| DOI | 10.1016/j.bmc.2023.117155 |
| 文献子类 | Article |
| 英文摘要 | Acute myeloid leukemia (AML) is characterized by fast progression and low survival rates, in which Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as driver mutations in a subgroup of AML patients. Herein, we describe the design, synthesis, and biological evaluation of a novel series of potent pyrido. [3,4-b]pyrazin-2(1H)-one derivatives as FLT3 inhibitors. The compounds exhibited moderate to potent FLT3 kinase inhibitory potency and excellent antiproliferative activities against MV4-11 cells. Among them, compound 13 demonstrated the most potent kinase activity against FLT3-D835Y (IC50 = 29.54 +/- 4.76 nM) and cellular potency against MV4-11 cells (IC50 = 15.77 +/- 0.15 nM). Compound 13 also efficiently inhibited the growth of multiple mutant BaF3 cells expressing FLT3-D835V/F, FLT3-F691L, and FLT3-ITD/D835Y. Furthermore, compound 13 was metabolically stable in mouse liver microsomes. Moreover, the treatment with compound 13 led to robust inhibition of FLT3 autophosphorylation on Tyr589/591 in MV4-11 cells. In summary, our data demonstrated that 13 was worthy of further study for the treatment of AML. |
| WOS关键词 | ACUTE MYELOID-LEUKEMIA ; INTERNAL TANDEM DUPLICATION ; MUTATIONS ; CHEMOTHERAPY ; CELLS |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000976920400001 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309720]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhou, Yubo; Li, Jia; Liu, Tao |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Sun, Mei,Wang, Chang,Wang, Peipei,et al. Design, synthesis, and evaluation of pyrido.[3,4-b]pyrazin-2(1H)-one derivatives as potent FLT3 inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2023,79:117155. |
| APA | Sun, Mei.,Wang, Chang.,Wang, Peipei.,Ye, Qingqing.,Zhou, Yubo.,...&Liu, Tao.(2023).Design, synthesis, and evaluation of pyrido.[3,4-b]pyrazin-2(1H)-one derivatives as potent FLT3 inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,79,117155. |
| MLA | Sun, Mei,et al."Design, synthesis, and evaluation of pyrido.[3,4-b]pyrazin-2(1H)-one derivatives as potent FLT3 inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 79(2023):117155. |
入库方式： OAI收割
来源：上海药物研究所
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