Identification of benzo[ b ]thiophene-1,1-dioxide derivatives as novel PHGDH covalent inhibitors
文献类型：期刊论文
| 作者 | Cao, Xin-Yu4; Li, Xinge2,3; Wang, Feng4; Duan, Yichen2; Wu, Xingmei4; Lin, Guo-Qiang4; Geng, Meiyu1,2,3 ; Huang, Min1,2; Tian, Ping4; Tang, Shuai1,2,4
|
| 刊名 | BIOORGANIC CHEMISTRY
 |
| 出版日期 | 2024-05-01 |
| 卷号 | 146页码:15 |
| 关键词 | Serine synthesis pathway PHGDH Stattic Covalent inhibitor Antitumor |
| ISSN号 | 0045-2068 |
| DOI | 10.1016/j.bioorg.2024.107330 |
| 通讯作者 | Tian, Ping(tianping@shutcm.edu.cn) ; Tang, Shuai(tangshuai@simm.ac.cn) ; Gao, Dingding(gaodingding@shutcm.edu.cn) |
| 英文摘要 | The increased de novo serine biosynthesis confers many advantages for tumorigenesis and metastasis. Phosphoglycerate dehydrogenase (PHGDH), a rate -limiting enzyme in serine biogenesis, exhibits hyperactivity across multiple tumors and emerges as a promising target for cancer treatment. Through screening our in-house compound library, we identified compound Stattic as a potent PHGDH inhibitor (IC 50 = 1.98 +/- 0.66 mu M). Subsequent exploration in structural activity relationships led to the discovery of compound B12 that demonstrated the increased enzymatic inhibitory activity (IC 50 = 0.29 +/- 0.02 mu M). Furthermore, B12 exhibited robust inhibitory effects on the proliferation of MDA-MB-468, NCI -H1975, HT1080 and PC9 cells that overexpress PHGDH. Additionally, using a [U - 13 C 6 ] -glucose tracing assay, B12 was found to reduce the production of glucose -derived serine in MDA-MB-468 cells. Finally, mass spectrometry -based peptide profiling, mutagenesis experiment and molecular docking study collectively suggested that B12 formed a covalent bond with Cys421 of PHGDH. |
| WOS关键词 | PHOSPHOGLYCERATE DEHYDROGENASE ; SERINE SYNTHESIS ; STAT3 ACTIVATION ; POOR-PROGNOSIS ; BREAST-CANCER ; METABOLISM ; CELLS ; EXPRESSION |
| 资助项目 | National Key R & D Program of China[2022YFF1202600] ; National Natural Science Foundation of China[22371188] ; National Natural Science Foundation of China[22071155] ; Open Project of Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs[SMECD2022003] ; Shanghai Municipal Education Commission[2019-01-07-00-10-E00072] ; Science and Technology Commission of Shanghai Municipality[20400750300] ; Science and Technology Commission of Shanghai Municipality[YDZX20233100004032] ; Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine[ZYYCXTD-D-202004] ; Shanghai Municipal Health Commission/Shanghai Municipal Administration of Traditional Chinese Medicine[ZY (2021-2023) -0501] ; Organizational Key R & D Program of SHUTCM[2023YZZ01] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001224191000001 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/311264]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Tian, Ping; Tang, Shuai; Gao, Dingding |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Beijing, Peoples R China 4.Shanghai Univ Tradit Chinese Med, Res Ctr Chiral Drugs, Shanghai Frontiers Sci Ctr TCM Chem Biol, Innovat Res Inst Tradit Chinese Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Cao, Xin-Yu,Li, Xinge,Wang, Feng,et al. Identification of benzo[ b ]thiophene-1,1-dioxide derivatives as novel PHGDH covalent inhibitors[J]. BIOORGANIC CHEMISTRY,2024,146:15. |
| APA | Cao, Xin-Yu.,Li, Xinge.,Wang, Feng.,Duan, Yichen.,Wu, Xingmei.,...&Gao, Dingding.(2024).Identification of benzo[ b ]thiophene-1,1-dioxide derivatives as novel PHGDH covalent inhibitors.BIOORGANIC CHEMISTRY,146,15. |
| MLA | Cao, Xin-Yu,et al."Identification of benzo[ b ]thiophene-1,1-dioxide derivatives as novel PHGDH covalent inhibitors".BIOORGANIC CHEMISTRY 146(2024):15. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。