Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists
文献类型：期刊论文
| 作者 | Shan, Bin6; Hou, Hui5,6; Zhang, Keke3,4; Li, Rui2,3,6; Shen, Chang1,2,6; Chen, Zhengyang5,6; Xu, Peijia4,6; Cui, Rongrong5,6 ; Su, Zhaoming4,6; Zhang, Changfa3,4,6
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2023-03-09 |
| 卷号 | 66期号:5页码:3327-3347 |
| DOI | 10.1021/acs.jmedchem.2c01714 |
| 文献子类 | Article |
| 英文摘要 | The development of stimulator of interferon genes (STING) agonists has been of potential applications for the treatment of cancer and infectious diseases. Based on the crystal structure of SR-717 bound to hSTING, we designed and synthesized a novel series of bipyridazine derivatives as highly potent STING agonists. Among them, compound 12L led to significant thermal stability shifts of the common alleles of hSTING, as well as that of mSTING. 12L also displayed potent activities in various hSTING alleles and mSTING competition binding assay. Specifically, 12L displayed higher cell-based activities than SR-717 in both human THP1 (EC50 = 0.38 +/- 0.03 mu M) and mouse RAW 264.7 cells (EC50 = 12.94 +/- 1.78 mu M), and was validated to activate the downstream signaling pathway of STING via a STING-dependent manner. Furthermore, compound 12L showed favorable pharmacokinetic (PK) properties and antitumor efficacy. These findings suggested that compound 12L has development potential as an antitumor agent. |
| WOS关键词 | CYCLIC GMP-AMP ; ACTIVATION ; PATHWAY ; ADAPTER ; MOUSE |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000935073800001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309694]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Fu, Wei; Jiang, Hualiang; Zhang, Sulin; Zheng, Mingyue |
| 作者单位 | 1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 2.China Pharmaceut Univ, Sch Pharm, Nanjing 211198, Peoples R China; 3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China; 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 6.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Shan, Bin,Hou, Hui,Zhang, Keke,et al. Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(5):3327-3347. |
| APA | Shan, Bin.,Hou, Hui.,Zhang, Keke.,Li, Rui.,Shen, Chang.,...&Zheng, Mingyue.(2023).Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists.JOURNAL OF MEDICINAL CHEMISTRY,66(5),3327-3347. |
| MLA | Shan, Bin,et al."Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists".JOURNAL OF MEDICINAL CHEMISTRY 66.5(2023):3327-3347. |
入库方式： OAI收割
来源：上海药物研究所
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