Discovery of a highly potent NPAS3 heterodimer inhibitor by covalently modifying ARNT
文献类型：期刊论文
| 作者 | Li, Peizhuo2,3; Tian, Yucheng4; Shang, Qinghong5; Tang, Cailing2,3; Hou, Zeng6; Li, Yuanqing2,3; Cao, Liyuan1; Xue, Shengyu2,3; Bian, Jinlei4; Luo, Cheng2,3
|
| 刊名 | BIOORGANIC CHEMISTRY
 |
| 出版日期 | 2023-10-01 |
| 卷号 | 139页码:10 |
| ISSN号 | 0045-2068 |
| 关键词 | NPAS3 Covalent inhibitor Protein -protein interaction 5-nitrothiazole warhead |
| DOI | 10.1016/j.bioorg.2023.106676 |
| 通讯作者 | Wu, Dalei(dlwu@sdu.edu.cn) ; Li, Zhiyu(zhiyuLi@cpu.edu.cn) ; Ding, Hong(hding@simm.ac.cn) |
| 英文摘要 | Neuronal PAS domain protein 3 (NPAS3), a basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) family member, is a pivotal transcription factor in neuronal regeneration, development, and related diseases, regulating the expression of downstream genes. Despite several modulators of certain bHLH-PAS family proteins being iden-tified, the NPAS3-targeted compound has yet to be reported. Herein, we discovered a hit compound BI-78D3 that directly blocks the NPAS3-ARNT heterodimer formation by covalently binding to the aryl hydrocarbon receptor nuclear translocator (ARNT) subunit. Further optimization based on the hit scaffold yielded a highly potent Compound 6 with a biochemical EC50 value of 282 & PLUSMN; 61 nM and uncovered the 5-nitrothiazole-2-sulfydryl as a cysteine-targeting covalent warhead. Compound 6 effectively down-regulated NPAS3's transcriptional function by disrupting the interface of NPAS3-ARNT complexes at cellular level. In conclusion, our study identifies the 5-nitrothiazole-2-sulfydryl as a cysteine-modified warhead and provides a strategy that blocks the NPAS3-ARNT heterodimerization by covalently conjugating ARNT Cys336 residue. Compound 6 may serve as a promising chemical probe for exploring NPAS3-related physiological functions. |
| WOS关键词 | GENE |
| 资助项目 | National Centre for Protein Science Shanghai (Protein Expression and Purification system) ; National Key R amp; D Program of China[2022YFC3400500] ; National Key R amp; D Program of China[2021ZD0203900] ; High-level new R amp; D institute[2019B090904008] ; High-level Innovative Research Institute[2021B0909050003] ; Department of Science and Technology of Guangdong Province |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| WOS记录号 | WOS:001037023200001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/306728]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Wu, Dalei; Li, Zhiyu; Ding, Hong |
| 作者单位 | 1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, 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, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China 5.Shandong Univ, State Key Lab Microbial Technol, Helmholtz Int Lab, Qingdao 266237, Peoples R China 6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310053, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Peizhuo,Tian, Yucheng,Shang, Qinghong,et al. Discovery of a highly potent NPAS3 heterodimer inhibitor by covalently modifying ARNT[J]. BIOORGANIC CHEMISTRY,2023,139:10. |
| APA | Li, Peizhuo.,Tian, Yucheng.,Shang, Qinghong.,Tang, Cailing.,Hou, Zeng.,...&Ding, Hong.(2023).Discovery of a highly potent NPAS3 heterodimer inhibitor by covalently modifying ARNT.BIOORGANIC CHEMISTRY,139,10. |
| MLA | Li, Peizhuo,et al."Discovery of a highly potent NPAS3 heterodimer inhibitor by covalently modifying ARNT".BIOORGANIC CHEMISTRY 139(2023):10. |
入库方式： OAI收割
来源：上海药物研究所
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