Discovery, structural optimization, and anti-tumor bioactivity evaluations of betulinic acid derivatives as a new type of ROR & gamma; antagonists
文献类型：期刊论文
| 作者 | Mei, Lianghe2,3; Xu, Lansong1,3,4,5; Wu, Sanan1,5; Wang, Yafang5; Xu, Chao1,5; Wang, Lin1,5; Zhang, Xingyu6; Yu, Chengcheng3; Jiang, Hualiang1,2,3,5 ; Zhang, Xianglei5
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2023-09-05 |
| 卷号 | 257页码:15 |
| ISSN号 | 0223-5234 |
| 关键词 | Betulinic acid ROR & gamma Target identification Rationale structure optimization Anti-tumor effects antagonists |
| DOI | 10.1016/j.ejmech.2023.115472 |
| 通讯作者 | Zhang, Xianglei(zhangxl6@shanghaitech.edu.cn) ; Bai, Fang(baifang@shanghaitech.edu.cn) ; Xie, Chengying(xiecy@lglab.ac.cn) |
| 英文摘要 | Betulinic acid (BA) is a natural pentacyclic triterpenoid that has a wide range of biological and pharmacological effects. Here, computational methods such as pharmacophore screening and reverse docking were used to predict the potential target for BA. Retinoic acid receptor-related orphan receptor gamma (ROR?) was confirmed as its target by several molecular assays as well as crystal complex structure determination. ROR? has been the focus of metabolic regulation, but its potential role in cancer treatment has only recently come to the fore. In this study, rationale optimization of BA was performed and several new derivatives were generated. Among them, the compound 22 showed stronger binding affinity with ROR? (K-D = 180 nM), good anti-proliferative activity against cancer cell lines, and potent anti-tumor efficacy with a TGI value of 71.6% (at a dose of 15 mg/kg) in the HPAF-II pancreatic cancer xenograft model. Further RNA-seq analysis and cellular validation experiments sup-ported that ROR? antagonism was closely related to the antitumor activity of BA and 22, resulting in suppression of the RAS/MAPK and AKT/mTORC1 pathway and inducing caspase-dependent apoptosis in pancreatic cancer cells. ROR? was highly expressed in cancer cells and tissues and positively correlated with the poor prognosis of cancer patients. These results suggest that BA derivatives are potential ROR? antagonists worthy of further exploration. |
| WOS关键词 | TH17 CELLS ; RECEPTOR ; APOPTOSIS ; DESIGN ; CANCER |
| 资助项目 | Major Research Plan of the National Natural Science Foundation of China[91953000] ; Natural Science Foundation of Shanghai[19ZR1467700] ; Lingang Laboratory[LG202101-01-06] ; Lingang Laboratory[22ZR1441400] ; Shanghai Science and Technology Development Funds[LG202102-01-03] ; Shanghai Science and Technology Development Funds[20QA1406400] ; National Natural Science Foundation of China[82003654] ; National Key Ramp;D Program of China[2022YFC3400501] ; start-up package from ShanghaiTech University ; Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at ShanghaiTech University ; HPC Platform of ShanghaiTech University |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| WOS记录号 | WOS:001011955900001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/306361]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhang, Xianglei; Bai, Fang; Xie, Chengying |
| 作者单位 | 1.Shanghai Tech 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, Drug Discovery & Dev Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.Univ Sci & Technol China, Affiliated Hosp USTC 1, Anhui Prov Hosp, Div Life Sci & Med, Hefei, Anhui, Peoples R China 5.Shanghai Tech Univ, Shanghai Inst Adv Immunochem Studies, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, China Suzhou Inst Drug Innovat, Suzhou 215123, Jiangsu, Peoples R China 7.Shanghai Clin Res & Trial Ctr, Shanghai 201210, Peoples R China 8.Lingang Lab, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Mei, Lianghe,Xu, Lansong,Wu, Sanan,et al. Discovery, structural optimization, and anti-tumor bioactivity evaluations of betulinic acid derivatives as a new type of ROR & gamma; antagonists[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,257:15. |
| APA | Mei, Lianghe.,Xu, Lansong.,Wu, Sanan.,Wang, Yafang.,Xu, Chao.,...&Xie, Chengying.(2023).Discovery, structural optimization, and anti-tumor bioactivity evaluations of betulinic acid derivatives as a new type of ROR & gamma; antagonists.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,257,15. |
| MLA | Mei, Lianghe,et al."Discovery, structural optimization, and anti-tumor bioactivity evaluations of betulinic acid derivatives as a new type of ROR & gamma; antagonists".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 257(2023):15. |
入库方式： OAI收割
来源：上海药物研究所
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