赵玉军 男 博导 中国科学院上海药物研究所
电子邮件: yjzhao@simm.ac.cn
通信地址: 上海市浦东新区祖冲之路555号
邮政编码: 201203
研究领域
课题组主要的研究方向是基于药物靶点,开发新颖的小分子化合物分子探针。研究分子探针的分子、细胞、和动物体内活性,探索其中优选的、具有高活性和类药性化合物的成药性,积极推进具有开发潜力药物的临床研究。
主要的研究领域是肿瘤和代谢性疾病。
1. 蛋白质相互作用和细胞凋亡及肿瘤免疫
针对MDM2/p53, MDM4/p53, BCL-2/BH3, BFL-1/BH3, PD-1/PD-L1等疾病相关的蛋白质相互作用药物靶标,基于靶点蛋白质结构和计算机辅助药物设计,合成优化小分子化合物,获得高活性、高选择性的先导化合物,在疾病模型中阐明其体内外药效和可成药性.
2. NIK激酶抑制剂对于肝脏损伤的保护作用研究
NFκB信号通路包括经典NFκB1信号通路和非经典NFκB2信号通路。经典NFκB1信号通路由p50和RelA(或RelC)二聚,进而能够启动基因转录;非经典NFκB2信号通路由p52和RelB二聚,进而能够启动基因转录。活化的NIK激酶可以促进p100降解生成为p52,进而激活NFκB2信号通路的基因转录。在肝硬化病人肝组织内,NIK mRNA水平升高;毒素和氧化应激也能够使得小鼠肝脏中NIK mRNA水平升高。NIK高表达会诱使肝细胞分泌炎症因子,造成炎症和组织坏死,从而导致小鼠死亡。我们的研究发现,利用小分子NIK激酶抑制剂,可以显著降低p52的蛋白水平,进而抑制NFκB2信号通路。在小鼠模型内,NIK激酶抑制剂B022可以抑制NFκB2信号通路,进而抑制炎症因子THFα,IL-6,CCL2,CCL5, CXCL5和氧化应激因子iNOS mRNA生成,显著减轻了毒素诱导的肝脏细胞调亡,延长了肝损伤小鼠的生存时间。我们的研究表明,NIK抑制剂具有治疗肝损伤的潜在药用价值。
3. 表观遗传 BET Bromodomain抑制剂的抗肿瘤活性研究
BET家族蛋白的Bromodomain结构域可以识别乙酰化赖氨酸,家族蛋白中的BRD4是连接组蛋白和RNA聚合酶II 的关键桥梁。最近的医学、生物学、药学研究成果表明,抑制BET Bromodomain的小分子化合物,可能被用于治疗BET Bromodomain调控异常引起的癌症、炎症、心脏功能衰竭和其他特定疾病,国际上相关的临床研究已经进行到二期阶段。我们开发了一类新颖的、具有较高选择性BET Bromodomain小分子抑制剂,在部分三阴性乳腺癌细胞内具有良好抗肿瘤活性。通过联合用药的方式,我们在具有原发性耐药的肿瘤细胞株内,提高了BET Bromodomain抑制剂的抗肿瘤活性。目前,这一类化合物的成药性深入研究正在进行之中。
招生信息
招收药物化学专业硕士生,博士生和对药物化学研究感兴趣、具有较好小分子合成功底的博士后
招生专业
招生方向
教育背景
教授课程
Module 1
Advance Organic Synthesis
指导学生
已指导学生
陈德恒 博士研究生 100701-药物化学
吴高星 硕士研究生 078001-药物化学
张希晨 硕士研究生 078001-药物化学
李志强 博士研究生 100701-药物化学
张世言 博士研究生 100701-药物化学
现指导学生
程靖 博士研究生 100701-药物化学
路宇航 博士研究生 100701-药物化学
周泽惠 博士研究生 100701-药物化学
王先城 硕士研究生 078001-药物化学
楼剑锋 博士研究生 100701-药物化学
吴非飞 博士研究生 100701-药物化学
论文
独立工作的论文 (Independent Research)
1. Jianfeng Lou, Qianqian Zhou, Xilin Lyu, Xinyi Cen, Chen Liu, Ziqin Yan, Yan Li, Haotian Tang, Qiupei Liu, Jian Ding, Ye Lu, He Huang,* Hua Xie,* Yujun Zhao,* Discovery of a covalent inhibitor that overcame resistance to Venetoclax in AML cells overexpressing BFL-1, Journal of Medicinal Chemistry, 2024, 67, DOI: 10.1021/acs.jmedchem.4c00291. (IF: 6.8, Year 2024)
2. Wenhua Zhu, Cuiting Liu, Kang Xi, Anqi Li, Lian Shen, Yana Li, Miaomiao Jia, Yangbo He, Gang Chen, Chenglong Liu, Yangqiang Chen, Kai Chen, Fan Sun, Daizhou Zhang, Chonggang Duan, Heng Wang, Dongdong Wang, Yujun Zhao,* Xiangjing Meng,* Di Zhu,* Discovery of Novel 1-Phenylpiperidine Urea-Containing Derivatives Inhibiting β-Catenin/BCL9 Interaction and Exerting Antitumor Efficacy Through the Activation of Antigen Presentation of cDC1 Cells, Journal of Medicinal Chemistry, 2024, 67, DOI: 10.1021/acs.jmedchem.3c02079. (IF: 6.8, Year 2024)
3. Zhitong Lin, Chen Liu, Ziqin Yan, Jing Cheng, Xiancheng Wang, Feilong Zhou, Xilin Lyu, Shiyan Zhang, Daizhou Zhang, Xiangjing Meng,* Yujun Zhao*, Synthesis and Biological Evaluation of 4-Imidazolidinone–Containing Compounds as Potent Inhibitors of the MDM2/p53 Interaction, European Journal of Medicinal Chemistry, 2024, 116366. (IF: 6.0, Year 2024)
4. Shaozhao Qin, Lijian Feng, Qingyi Zhao, Ziqin Yan, Xilin Lyu, Kaige Li, Baiyang Mu, Yujie Chen, Weiwei Lu, Chao Wang, Yanrui Suo, Jinfeng Yue, Mengqing Cui, Yingjie Li, Yujun Zhao,* Zhiqiang Duan,* Jidong Zhu,* and Xiaojie Lu,* Discovery and Optimization of WDR5 Inhibitors via Cascade 2 Deoxyribonucleic Acid-Encoded Library Selection Approach, Journal of Medicinal Chemistry, 2024, 67, 1079-1092. (IF: 6.8, Year 2024)
5. Jing Cheng, Ziqin Yan, Xinzhi Li, Chen Liu, Linjiang Tong, Xilin Lyu, Bingjie Yang, Zheng Chen,* Yujun Zhao*, Structure-based optimization of indoline-containing compounds as second generation inhibitors of NF-κB-inducing kinase (NIK). Journal of Molecular Structure, 2024, 136755. (IF: 4.0, Year 2024)
6. Jing Cheng, Ziqin Yan, Kailong Jiang, Chen Liu, Dehua Xu, Xilin Lyu, Xiaobei Hu, Shiyan Zhang, Yubo Zhou,* Jia Li,* Yujun Zhao*, Discovery of JN122, a Spiroindoline-containing Molecule, that Inhibits MDM2/p53 Protein-protein Interaction and Exerts Robust in vivo Antitumor Efficacy. Journal of Medicinal Chemistry, 2023, 66, 16991-17025. (IF: 7.3, Year 2023)
7. Ziqin Yan, Xilin Lyu, Dongze Lin, Gaoxing Wu, Yang Gong, Xuelian Ren, Jian Xiao, Jianfeng Lou, He Huang, Yi Chen*, Yujun Zhao*, Selective degradation of cellular BRD3 and BRD4-L promoted by PROTAC molecules in six cancer cell lines, European Journal of Medicinal Chemistry, 2023, 115381. (IF: 6.7, Year 2023)
8. Ying Cheng, Xilin Lyu, Chen Liu, Xiancheng Wang, Jing Cheng, Daizhou Zhang, Xiangjing Meng,* Yujun Zhao*, Synthesis and biological evaluation of sclareolide-indole conjugates and their derivatives. Molecules, 2023, 28, 1737. (IF: 4.92, Year 2022)
9. Mengnisa Seydimemet, Yixuan Yang, Yuhan Lv, Jiaxiang Liu, Ziqin Yan, Yujun Zhao*, Xuan Wang*, Xiaojie Lu*, Design, construction, and screening of diversified pyrimidine-focused DNA-encoded libraries, ACS Med. Chem. Lett. 2023, 14, 1073−1078. (IF: 4.2, Year 2022)
10. Shiyan Zhang, Ziqin Yan, Yafang Li, Yang Gong, Xilin Lyu, Jianfeng Lou, Daizhou Zhang, Xiangjing Meng*, Yujun Zhao*, Structure-based discovery of MDM2/4 dual inhibitors that exert antitumor activities against MDM4 -overexpressing cancer cells, Journal of Medicinal Chemistry, 2022, 65, 6207-6230. (IF: 8.03, Year 2022)
11. Xuexin Feng, Ziqin Yan, Feilong Zhou, Jianfeng Lou, Xilin Lyu, Xuelian Ren, Ziyu Zeng, Chenglong Liu, Shiyan Zhang, Di Zhu, He Huang, Jinming Yang*, Yujun Zhao*, Discovery of a selective and covalent small-molecule inhibitor of BFL-1 protein that induces robust apoptosis in cancer cells, European Journal of Medicinal Chemistry, 2022, 114327. (IF: 7.08, Year 2022)
12. Jianfeng Lou, Yuhang Lu, Jing Cheng, Feilong Zhou, Ziqin Yan, Daizhou Zhang, Xiangjing Meng,* Yujun Zhao*, A chemical perspective on the modulation of TEAD transcriptional activities: Recent progress, challenges, and opportunities, European Journal of Medicinal Chemistry, 2022, 114684. (IF: 7.08, Year 2022)
13. Shiyan Zhang, Jianfeng Lou, Yafang Li, Feilong Zhou, Ziqin Yan, Xilin Lyu, Yujun Zhao*, Recent progress and clinical development of inhibitors that block MDM4/p53 protein-protein interactions, Journal of Medicinal Chemistry, 2021, 64, 10621–10640. (IF: 7.44, Year 2021)
14. Chenglong Liu, Feilong Zhou, Ziqin Yan, Lian Shen, Xichen Zhang, Fenglian He, Xiaojie Lu, Heng Wang, Ker Yu, Yujun Zhao*, Di Zhu*, Discovery of a novel, potent, and selective small-molecule inhibitor of PD-1/PD-L1 interaction with robust in vivo anti-tumor efficacy, British Journal of Pharmacology, 2021, 178, 2651-2670. (IF: 8.73, Year 2021)
15. Xuan Wang, Jiaxiang Liu, Ziqin Yan, Xiaohong Liu, Sixiu Liu, Yanrui Suo, Weiwei Lu, Jinfeng Yue, Kaixian Chen, Hualiang Jiang, Yujun Zhao*, Mingyue Zheng*, Dongcheng Dai*, Xiaojie Lu*, Diversified strategy for the synthesis of DNA-encoded oxindole libraries, Chemical Science, 2021, 12, 2841-2847. (IF: 9.82, Year 2021)
16. Jing Cheng, Xuexin Feng, Zhiqiang Li, Feilong Zhou, Jin-Ming Yang, Yujun Zhao*, Pharmacological inhibition of NF-κB-inducing Kinase (NIK) with small molecules for the treatment of human diseases, RSC Medicinal Chemistry, 2021, 12, 552-565.
17. Xian Zhou, Xuexin Feng, Dachi Wang, Deheng Chen, Gaoxing Wu, Ziqin Yan, Xilin Lyu, Huan Wang, Jin-Ming Yang,* Yujun Zhao*, Synthesis and bioactivity studies of covalent inhibitors derived from (-)-Chaetominine, Journal of Molecular Structure, 2021, 1241, 130694. (IF: 3.19, Year 2021)
18. Xinzhi Li, Bingchuan Yuan, Min Lu , Yuqin Wang, Na Ding, Chunhong Liu, Ming Gao, Zhicheng Yao, Shiyan Zhang, Yujun Zhao, Liwei Xie, Zheng Chen*, The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression, Nature Communications, 2021, 12, 7213.
19. Zhiqiang Li, Xinzhi Li, Ming-Bo Su, Li-Xin Gao, Yu-Bo Zhou, Bingchuan Yuan, Xilin Lyu, Ziqin Yan, Chujiao Hu, Hao Zhang, Cheng Luo, Zheng Chen*, Jia Li*, Yujun Zhao*, Discovery of a potent and selective NF-κB-inducing kinase (NIK) inhibitor that has anti-inflammatory effects in vitro and in vivo, Journal of Medicinal Chemistry, 2020, 63, 4388-4407. (IF: 7.44, Year 2021)
20. Shiyan Zhang, Chaoying Huang, Xilin Lyu, Peipei Wang, Yi Zang, Zengtao Wang, Huan Wang, Jia Li*, Yujun Zhao*, Discovery of a 2-pyridinyl urea-containing compound YD57 as a potent inhibitor of apoptosis signal -regulating kinase 1 (ASK1), European Journal of Medicinal Chemistry, 2020, 195, 112277. (IF: 6.51, Year 2021)
21. Xinzhi Li, Yongsen Wu, Yue Song, Na Ding, Min Lu, Linna Jia, Yujun Zhao, Ming Liu, Zheng Chen*, Activation of NF-kB-inducing kinase in islet β-cells causes β-cell failure and diabetes, Molecular Therapy, 2020, 2430-2441. (IF: 11.45, Year 2021)
22. Deheng Chen, Tian Lu, Ziqin Yan, Wenchao Lu, Feilong Zhou, Xilin Lyu, Biling Xu, Hualiang Jiang, Kaixian Chen, Cheng Luo*, and Yujun Zhao*, Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins, European Journal of Medicinal Chemistry, 2019, 182, 111633. (IF: 6.51, Year 2021)
23. Erbao Zhao, Feilong Zhou, and Yujun Zhao*, Lewis Acids Promoted 3+2 Cycloaddition of Oxaziridines and Cyclic Allylic Alcohols through Carbonyl Imine Intermediates, Journal of Organic Chemistry, 2019, 84 (7), 4282–4293. (IF: 4.35, Year 2021 )
24. Deheng Chen, Dexiang Guo, Ziqin Yan, Yujun Zhao*, Allenamide as a bioisostere of acrylamide in design and synthesis of targeted covalent inhibitors Med. Chem. Commun. 2018, 9, 244-253. (IF: 2.80, Year 2020)
25. Feilong Zhou, Erbao Zhao, Ziqin Yan, Deheng Chen, Yujun Zhao*, Synthesis of 3,4-diarylsubstituted hexahydro-1H-indoles, Tetrahedron Letters, 2018, 59, 1871-1874. (IF: 2.41, Year 2021)
26. Xiaomeng Ren, Xinzhi Li, Linna Jia, Deheng Chen, Hai Hou, Liangyou Rui, Yujun Zhao*, Zheng Chen*, A small-molecule inhibitor of NF-kB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury, FASEB Journal. 2017, 2, 711-718. (IF: 5.19, Year 2021)
专利
独立研究工作专利 (Patents Based on Independent Research):
1. 赵玉军,程靖,严子琴,吕细林,张世言,周飞龙,具有取代苯基螺[吲哚啉-3,3'-吡咯烷]结构的小分子化合物,PCT专利优先权申请号: WO202211255892.0;申请日期:2022-10-14;
2. 赵玉军,朱棣,周飞龙,严子琴,刘成龙,曾子余,程颖,具有苄氧基芳基醚结构的化合物及其制备方法和用途,PCT专利优先权申请号:WO202210220889.9;申请日期:2022-03-09;
3. 赵玉军,张世言,严子琴,吕细林,周飞龙,具有4-(取代氨甲基)-5-新戊基-N-取代基吡咯烷-2-甲酰胺结构的化合物,PCT专利优先权申请号: WO202111571938.5;申请日期:2021-12-21;
4. 赵玉军,张世言,严子琴,吕细林,程靖,周飞龙,巩洋,具有取代苯基螺[吲哚啉-3,3’-吡咯烷]结构的小分子化合物,PCT专利申请号: WO2022218379;申请日期:2021-04-15;
5. 赵玉军,李志强,严子琴,李亚芳,吕细林,周飞龙,苯并含氮五元杂环化合物及其合成和应用,中国专利申请号:202110476362.8;申请日期:2021-04-30;
6. 赵玉军,朱棣,周飞龙, 严子琴,刘成龙,张希晨, 一种具有苄氧基芳环结构的化合物,其制备方法和用途, PCT专利申请号: WO2020244518, 申请日期: 2020-06-02; 中国专利号: ZL202010491651.0,申请日期: 2020-06-03
7. 赵玉军,王欢,陈德恒,周飞龙, 严子琴,吕细林,具有2H-吲唑结果的小分子化合物及其合成和应用,中国专利号: ZL202010135402.8, 申请日期: 2020.03.02
8. 赵玉军、李佳、王增涛、张世言、臧奕、王培培、孙丹丹、张含烟, 2-吡啶取代脲结构小分子化合物及其合成和应用,中国专利申请号: 201910716810.X, 申请日期: 2019-08-05
9. 赵玉军、陈德恒、郭德祥、严子琴、周飞龙、耿美玉、丁健、沈爱军、刘红椿、张敏敏,一种BRD4 抑制剂及其制备和应用, 中国专利号: ZL201880024931.1, 申请公布日期: 2018-04-13; PCT专利公布号: WO2018/188660, 公布日期: 2018-10-18;
10. 赵玉军,李志强,严子琴,李佳,周宇波,苏明波,陈政,一种具有2-氨基嘧啶结构的化合物,其制备方法和用途,中国专利申请号: 201811381899.0,申请日期: 2018-11-20;
11. 赵玉军、郭德祥、严子琴,含有共轭联烯酰胺结构的化合物、其制备方法、药物组合物和用途, 中国专利号: ZL201711105956.8, 申请日期: 2017-11-10;
12. 赵玉军、陈德恒、严子琴,郭德祥,含有共轭联烯结构的化合物、其药物组合物和用途, 中国专利号: ZL201710639753.0, 申请日期: 2017-07-31.
署名专利 (Co-author Patents):
1. Shaomeng Wang*, Yujun Zhao, Bing Zhou, Angelo Aguilar, Liu Liu, Longchuan Bai, Donna McEachern, Duxin Sun, Bo Wen, Ruijuan Luo, and Ting Zhao, 9H-Pyrimido[4,5-B]indoles and Related Analogs as BET Bromodomain Inhibitors, 2015.2, PCT Patent Publication No.: WO2015131005 A1; US Patent No.: US9580430B2 (2017-02-28), US10253044B2 (2019-04-09).
2. Shaomeng Wang*, Xu Ran, Yujun Zhao, Chao-Yie Yang, Liu Liu, Longchuan Bai, Donna McEachern, Jeanne Stuckey, Jennifer Lynn Meagher, Duxin Sun, Xiaoqin Li, Bing Zhou, Hacer Karatas, Ruijuan Luo, Arul Chinnaiyan, Irfan A. Asangani, BET Bromodomain Inhibitors and therapeutic Methods Using the same, 2014.10.9, PCT Patent Publication No.: WO2014164596 A1; China Patent No.: CN105377851B (2018-07-20); US Patent No.: US9675697B2 (2017-06-13), US10391175B2 (2019-08-27).
3. Shaomeng Wang*, Yujun Zhao, Wei Sun, Sanjeev Kumar, Lance Leopold, Laurent Debussche, Cedric Barriere, Jeanchristophe Carry, Kwame Amaning, Spiro-Oxindole MDM2 Antagonists, 2012.5.18, PCT Patent Publication No.: WO 2012/065022 A2; US Patent No.: CN103298818B (2016.6.29); US Patent No.: US9302120B2 (2016-04-05)
4. Shaomeng Wang*, Shanghai Yu, Wei Sun, Sanjeev Kumar Shangary, Duxin Sun, Peng Zou, Donna McEachern, Yujun Zhao, Spiro-Oxindole MDM2 Antagonists, 2011.5.19, PCT Patent Publication No.: WO 2011060049; China Patent No.: CN102712650 B (2015-05-20); US Patent No.: US8518984 B2 (2013.8.27); US8877796B2 (2014-11-04).
5. Shaomeng Wang*, Jianyong Chen, Yujun Zhao, Cindy Gomez, Longchuan Bai, Zeneta Nikolovska-Coleska, STAT3 Ligands and Therapeutic Uses Thereof, 2010.7.8, PCT Patent Publication No.: WO 2010077589; US Patent Publication No.: US 2011/0319362; China Patent Publication No.: CN 200980156486; European Patent Publication No.: EP2373658 A4
6. Teck-Peng Loh*, Yujun Zhao, Cyclization Process of Forming a Multiple Ring Compound. 2007.2, PCT Patent Publication No.: WO 2007097719; US Patent No.: US8227645 B2 (2012.1.4);