Discovery and Biological evaluation of pyrimido[4,5-d] pyrimidine-2,4(1H, 3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors
文献类型：期刊论文
| 作者 | Diao, Yanyan1; Fang, Xiaoyu1; Song, Peiran2,3,4; Lai, Mengzhen2,3,5; Tong, Linjiang2,3; Hao, Yongjia1; Dou, Dou1; Liu, Yingqiang2,3; Ding, Jian2,3,4 ; Zhao, Zhenjiang1
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2019-08-01 |
| 卷号 | 27期号:15页码:3390-3395 |
| 关键词 | Bruton's tyrosine kinase B-cell malignancies Potent inhibitors Structure-activity relationship Cellular activities |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2019.06.023 |
| 通讯作者 | Zhao, Zhenjiang(zhjzhao@ecust.edu.cn) ; Xie, Hua(hxie@simm.ac.cn) ; Li, Honglin(hlli@ecust.edu.cn) |
| 英文摘要 | Aberrant activation of B cell receptor (BCR) signal transduction cascade contributes to the propagation and maintenance of B cell malignancies. The discovery of mall molecules with high potency and selectivity against Bruton's tyrosine kinase (BTK), a key signaling molecule in this cascade, is particularly urgent in modern treatment regimens. Herein, a series of pyrimido[ 4,5-d] pyrimidine-2,4(1H, 3H)-dione derivatives were reported as potent BTK inhibitors. Compounds 17 and 18 displayed strong BTK inhibitory activities in the enzymatic inhibition assay, with the IC50 values of 1.2 and 0.8 nM, respectively, which were comparable to that of ibrutinib (IC50 = 0.6 nM). Additionally, compound 17 had a more selective profile over EGFR than ibrutinib. According to the putative binding poses, the molecular basis of this series of compounds with respect to potency against BTK and selectivity over EGFR was elucidated. In further experiments at cellular level, compounds 17 and 18 significantly inhibited the proliferation of Ramos and TMD8 cells. And they arrested 75.4% and 75.2% of TMD8 cells in G1 phase, respectively, at the concentration of 1 mu M. |
| WOS关键词 | BTK INHIBITORS ; ACTIVATION ; TARGET ; TEC |
| 资助项目 | National Key Research and Development Program[2016YFA0502304] ; National Natural Science Foundation of China[81825020] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; Fundamental Research Funds for the Central Universities ; National Program for Special Supports of Eminent Professionals ; National Program for Support of Top-Notch Young Professionals |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000476649400020 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/289227]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhao, Zhenjiang; Xie, Hua; Li, Honglin |
| 作者单位 | 1.East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 5.Nanchang Univ, Sch Pharm, 461 Bayi Rd, Nanchang 330006, Jiangxi, Peoples R China |
| 推荐引用方式 GB/T 7714 | Diao, Yanyan,Fang, Xiaoyu,Song, Peiran,et al. Discovery and Biological evaluation of pyrimido[4,5-d] pyrimidine-2,4(1H, 3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2019,27(15):3390-3395. |
| APA | Diao, Yanyan.,Fang, Xiaoyu.,Song, Peiran.,Lai, Mengzhen.,Tong, Linjiang.,...&Li, Honglin.(2019).Discovery and Biological evaluation of pyrimido[4,5-d] pyrimidine-2,4(1H, 3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,27(15),3390-3395. |
| MLA | Diao, Yanyan,et al."Discovery and Biological evaluation of pyrimido[4,5-d] pyrimidine-2,4(1H, 3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 27.15(2019):3390-3395. |
入库方式： OAI收割
来源：上海药物研究所
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