Design, synthesis and structure-activity relationship studies of pyrido [2,3-d]pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors & nbsp;
文献类型：期刊论文
| 作者 | Su, Wenhong5,6; Chen, Zhiwen4; Liu, Meiying6; He, Rui4; Liu, Chaoyi6; Li, Rui3; Gao, Mingshan6; Zheng, Mingyue3 ; Tu, Zhengchao2; Zhang, Zhang4
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
 |
| 出版日期 | 2022-05-15 |
| 卷号 | 64页码:7 |
| 关键词 | JAK3 Covalent inhibitor Anti-cancer activity Selectivity |
| ISSN号 | 0960-894X |
| DOI | 10.1016/j.bmcl.2022.128680 |
| 通讯作者 | Zhang, Zhang(zhang_zhang@jnu.edu.cn) ; Xu, Tianfeng(tfxu@simm.ac.cn) |
| 英文摘要 | Aberrantly activated Janus kinase 3 (JAK3) has been constantly detected in various immune disorders and hematopoietic cancers, suggesting its potential of being an attractive therapeutic target for these indications. Clinical benefits of drugs selectively targeting JAK3 versus pan-JAK inhibitors remain unclear. In this study, we report the design and synthesis of a new series of JAK3 covalent inhibitors with a pyrido[2,3-d]pyrimidin-7-one scaffold. After the extensive SAR study, compound 10f emerged to be the most potent JAK3 inhibitor with an IC50 value of 2.0 nM. It showed excellent selectively proliferation inhibitory activity against U937 cells harboring JAK3 M511I mutation, while remained weakly active to the other tested cancer cells. Compound 10f also dose dependently inhibited the phosphorylation of JAK3 and its downstream signal STAT5 in U937 cells. Taken together, 10f may serve as a promising tool molecule for treating cancers with aberrantly activated JAK3.& nbsp; |
| WOS关键词 | INHIBITION ; MUTATIONS |
| 资助项目 | Shanghai Pujiang Program[19PJ1411400] ; National Ministry of Science and Technology[SQ2019YFE010401] ; Na-tional Natural Science Foundation of China[81973158] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000791828500005 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/301083]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Zhang; Xu, Tianfeng |
| 作者单位 | 1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 2.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, 190 Kaiyuan Ave,Guangzhou Sci Pk, Guangzhou 510530, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.Jinan Univ, Coll Pharm, Int Cooperat Lab Tradit Chinese Med Modernizat &, Minist Educ MoE, 601 Huangpu Ave West, Guangzhou 510632, Peoples R China 5.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 |
Su, Wenhong,Chen, Zhiwen,Liu, Meiying,et al. Design, synthesis and structure-activity relationship studies of pyrido [2,3-d]pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors & nbsp; [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2022,64:7. |
| APA |
Su, Wenhong.,Chen, Zhiwen.,Liu, Meiying.,He, Rui.,Liu, Chaoyi.,...&Xu, Tianfeng.(2022). Design, synthesis and structure-activity relationship studies of pyrido [2,3-d]pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors & nbsp; .BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,64,7. |
| MLA |
Su, Wenhong,et al." Design, synthesis and structure-activity relationship studies of pyrido [2,3-d]pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors & nbsp; ".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 64(2022):7. |
入库方式： OAI收割
来源：上海药物研究所
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