Discovery of a brain-permeable bromodomain and extra terminal domain (BET) inhibitor with selectivity for BD1 for the treatment of multiple sclerosis
文献类型：期刊论文
| 作者 | Chen, Xuetao1,2,4; Wu, Tingting1,2,4; Du, Zhiyan3; Kang, Wenjing1,2,4; Xu, Rujun1,2,4; Meng, Fanying1,2,4; Liu, Chihong1,2,4; Chen, Yali1,2,4; Bao, Qichao1,2; Shen, Jingkang3 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2024-02-05 |
| 卷号 | 265页码:14 |
| ISSN号 | 0223-5234 |
| 关键词 | BET BD1 Bromodomain Brain-permeable Multiple sclerosis |
| DOI | 10.1016/j.ejmech.2023.116080 |
| 通讯作者 | Cao, Danyan(caody@simm.ac.cn) ; Jiang, Zhengyu(jiangzhengyucpu@163.com) ; Guo, Xiaoke(kexin95@126.com) |
| 英文摘要 | Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease and lacks effective therapeutic agents. Dysregulation of transcription mediated by bromodomain and extra-terminal domain (BET) proteins containing two different bromodomains (BD1 and BD2) is an important factor in multiple diseases, including MS. Herein, we identified a series of BD1-biased inhibitors, in which compound 16 showed nanomolar potency for BD1 (Kd = 230 nM) and a 60-fold selectivity for BRD4 BD1 over BD2. The co-crystal structure of BRD4 BD1 with 16 indicated that the hydrogen bond interaction of 16 with BD1-specific Asp145 is important for BD1 selectivity. 16 showed favorable brain distribution in mice and PK properties in rats. 16 was able to inhibit microglia activation and had significant therapeutic effects on EAE mice including improvement of spinal cord inflammatory conditions and demyelination protection. Overall, these results suggest that brain-permeable BD1 inhibitors have the potential to be further investigated as therapeutic agents for MS. |
| WOS关键词 | DRUG DISCOVERY ; TARGETING BROMODOMAIN ; POTENT ; DERIVATIVES ; MODELS ; FAMILY ; SERIES ; BROMO ; IDENTIFICATION ; OPTIMIZATION |
| 资助项目 | National Natural Science Foundation of China[81930100] ; National Natural Science Foundation of China[82173680] ; Jiangsu Province Funds for Distinguished Young Scientists[BK20220087] ; Young Elite Scientists Sponsorship Program by CAST, China[YESS20180146] ; Jiangsu Funding Program for Excellent Postdoctoral Talent[2023ZB486] ; China Postdoctoral Science Foundation[2023M743900] ; Fundamental Research Funds for the Central Universities[2632023GR14] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| WOS记录号 | WOS:001145271700001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/308763]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Cao, Danyan; Jiang, Zhengyu; Guo, Xiaoke |
| 作者单位 | 1.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China 2.China Pharmaceut Univ, Jiang Su Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 210009, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Xuetao,Wu, Tingting,Du, Zhiyan,et al. Discovery of a brain-permeable bromodomain and extra terminal domain (BET) inhibitor with selectivity for BD1 for the treatment of multiple sclerosis[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,265:14. |
| APA | Chen, Xuetao.,Wu, Tingting.,Du, Zhiyan.,Kang, Wenjing.,Xu, Rujun.,...&Guo, Xiaoke.(2024).Discovery of a brain-permeable bromodomain and extra terminal domain (BET) inhibitor with selectivity for BD1 for the treatment of multiple sclerosis.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,265,14. |
| MLA | Chen, Xuetao,et al."Discovery of a brain-permeable bromodomain and extra terminal domain (BET) inhibitor with selectivity for BD1 for the treatment of multiple sclerosis".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 265(2024):14. |
入库方式： OAI收割
来源：上海药物研究所
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