Structure-Based Rational Design and Evaluation of BET-Aurora Kinase Dual-Inhibitors for Treatment of Cancers
文献类型：期刊论文
| 作者 | Lyu, Kaikai1,4; Ren, Ying3; Mou, Jie3; Yang, Yunfang3; Pan, Yaoyao3; Zhang, Huijie1,4; Li, Yanlian4; Cao, Danyan4; Chen, Lin4; Chen, Danqi1,4
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2024-12-31 |
| 页码 | 21 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.4c01933 |
| 通讯作者 | Chen, Danqi(dqchen@simm.ac.cn) ; Guo, Dong(guo@xzhmu.edu.cn) ; Xiong, Bing(bxiong@simm.ac.cn) |
| 英文摘要 | Simultaneous inhibition of the bromodomain and extra-terminal domain and Aurora kinases is a promising anticancer therapeutic strategy. Based on our previous study on BET-kinase dual inhibitors, we employed the molecular docking approach to design novel dual BET-Aurora kinase A inhibitors. Through several rounds of optimization and with the guidance of the solved cocrystal structure of BRD4 bound to inhibitor 27, we finally obtained a series of highly potent dual BET-Aurora kinase A inhibitors. Compound 38 exhibited strong affinity toward both BRD4 and Aurora kinase A. It also showed good antiproliferative activities on diverse cancer cell lines, good pharmacokinetic profiles, and favorable antitumor efficacy in renal cell cancer and colon cancer xenograft models with TGI of 45.99% and 53.06%, respectively. The development of compound 38 reinforces the concept that a rational design may achieve dual inhibitors targeting specific kinases and bromodomain proteins. |
| WOS关键词 | BROMODOMAIN INHIBITORS ; ACQUIRED-RESISTANCE ; DRUG DISCOVERY ; BRD4 ; POTENT ; MYC ; IDENTIFICATION ; STABILIZATION ; PHARMACOLOGY ; STATISTICS |
| 资助项目 | National Natural Science Foundation of China[2018ZX09711002-011-018] ; National Natural Science Foundation of China[2018ZX09711002-004] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[81330076] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[22377103] ; National Natural Science Foundation of China[BK20200106] ; Natural Science Foundation of Jiangsu Province |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001386275600001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/315306]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Chen, Danqi; Guo, Dong; Xiong, Bing |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China 3.Xuzhou Med Univ, Sch Pharm, Jiangsu Key Lab New Drug & Clin Pharm, Xuzhou 221006, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lyu, Kaikai,Ren, Ying,Mou, Jie,et al. Structure-Based Rational Design and Evaluation of BET-Aurora Kinase Dual-Inhibitors for Treatment of Cancers[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:21. |
| APA | Lyu, Kaikai.,Ren, Ying.,Mou, Jie.,Yang, Yunfang.,Pan, Yaoyao.,...&Xiong, Bing.(2024).Structure-Based Rational Design and Evaluation of BET-Aurora Kinase Dual-Inhibitors for Treatment of Cancers.JOURNAL OF MEDICINAL CHEMISTRY,21. |
| MLA | Lyu, Kaikai,et al."Structure-Based Rational Design and Evaluation of BET-Aurora Kinase Dual-Inhibitors for Treatment of Cancers".JOURNAL OF MEDICINAL CHEMISTRY (2024):21. |
入库方式： OAI收割
来源：上海药物研究所
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