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The discovery of a non-competitive GOT1 inhibitor, hydralazine hydrochloride, via a coupling reaction-based high-throughput screening assay

文献类型：期刊论文

作者Wu, Qiqi4,5; Sun, Zhongya3,4; Chen, Zhifeng4; Liu, Jingqiu4; Ding, Hong4; Luo, Cheng4,5; Wang, Mingliang1,2; Du, Daohai4,5
刊名BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
出版日期2022-10-01
卷号73页码:6
关键词Glutamate oxaloacetate transaminase 1 Inhibitor Hydralazine hydrochloride High -throughput screening
ISSN号0960-894X
DOI10.1016/j.bmcl.2022.128883
通讯作者Wang, Mingliang(wangmingliang@simm.ac.cn) ; Du, Daohai(dhdu@simm.ac.cn)
英文摘要Glutamate oxaloacetate transaminase 1 (GOT1) plays a key role in aberrant glutamine metabolism. GOT1 suppression can arrest tumor growth and prevent the development of cancer, indicating GOT1 as a potential anticancer target. Reported GOT1 inhibitors, on the other hand, are quite restricted. Here, we developed and optimized a coupling reaction-based high-throughput screening assay for the discovery of GOT1 inhibitors. By using this screening assay, we found that the cardiovascular drug hydralazine hydrochloride inhibited GOT1 catalytic activity, with an IC50 of 26.62 +/- 7.45 mu M, in a non-competitive and partial-reversible manner. In addition, we determined the binding affinity of hydralazine hydrochloride to GOT1, with a Kd of 16.54 +/- 8.59 mu M, using a microscale thermophoresis assay. According to structure-activity relationship analysis, the inhibitory activity of hydralazine hydrochloride is mainly derived from its hydrazine group. Furthermore, it inhibits the proliferation of cancer cells MCF-7 and MDA-MB-468 with a slight inhibitory effect compared to other tested cancer cells, highlighting GOT1 as a promising therapeutic target for the treatment of breast cancer.
WOS关键词CANCER ; TRANSAMINASE ; GLUTAMINE ; METABOLISM ; HALLMARKS
WOS研究方向Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000830848400003
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/301998]  
专题新药研究国家重点实验室
通讯作者Wang, Mingliang; Du, Daohai
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528437, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
3.Harbin Inst Technol, Sch Life Sci & Technol, Harbin 200092, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Ctr Chem Biol,State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, 138 Xianlin Rd, Nanjing 210023, Jiangsu, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Qiqi,Sun, Zhongya,Chen, Zhifeng,et al. The discovery of a non-competitive GOT1 inhibitor, hydralazine hydrochloride, via a coupling reaction-based high-throughput screening assay[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2022,73:6.
APA Wu, Qiqi.,Sun, Zhongya.,Chen, Zhifeng.,Liu, Jingqiu.,Ding, Hong.,...&Du, Daohai.(2022).The discovery of a non-competitive GOT1 inhibitor, hydralazine hydrochloride, via a coupling reaction-based high-throughput screening assay.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,73,6.
MLA Wu, Qiqi,et al."The discovery of a non-competitive GOT1 inhibitor, hydralazine hydrochloride, via a coupling reaction-based high-throughput screening assay".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 73(2022):6.

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来源：上海药物研究所

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