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
文献类型：期刊论文
| 作者 | Zhu, Wenhua6,7,8; Liu, Cuiting6,7,8; Xi, Kang6,7,8; Li, Anqi5; Shen, Li-an5; Li, Yana6,7,8; Jia, Miaomiao6,7,8; He, Yangbo6,7,8; Chen, Gang6,7,8; Liu, Chenglong5 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2024-06-24 |
| 页码 | 36 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.3c02079 |
| 通讯作者 | Zhao, Yujun(yjzhao@simm.ac.cn) ; Meng, Xiangjing(fredamxj@163.com) ; Zhu, Di(zhudi@fudan.edu.cn) |
| 英文摘要 | Aberrant activation of the Wnt/beta-catenin signaling is associated with tumor development, and blocking beta-catenin/BCL9 is a novel strategy for oncogenic Wnt/beta-catenin signaling. Herein, we presented two novel beta-catenin variations and exposed conformational dynamics in several beta-catenin crystal structures at the BCL9 binding site. Furthermore, we identified a class of novel urea-containing compounds targeting beta-catenin/BCL9 interaction. Notably, the binding modalities of inhibitors were greatly affected by the conformational dynamics of beta-catenin. Among them, 28 had a strong affinity for beta-catenin (K-d = 82 nM), the most potent inhibitor reported. In addition, 13 and 35 not only activate T cells but also promote the antigen presentation of cDC1, showing robust antitumor efficacy in the CT26 model. Collectively, our study demonstrated a series of potent small-molecule inhibitors targeting beta-catenin/BCL9, which can enhance antigen presentation and activate cDC1 cells, delivering a potential strategy for boosting innate and adaptive immunity to overcome immunotherapy resistance. |
| WOS关键词 | SMALL-MOLECULE INHIBITORS ; PROTEIN-PROTEIN INTERACTION ; SIGNALING PATHWAY ; CRYSTAL-STRUCTURE ; BETA-CATENIN ; CANCER ; COMPLEX ; DESIGN ; TARGET ; IMMUNE |
| 资助项目 | Jinan innovation team[2020GXRC041] ; Jinan innovation team[2021GXRC069] ; Jinan innovation team[202228051] ; National Natural Science Foundation of China[81872895] ; National Natural Science Foundation of China[82073881] ; Shanghai Science and Technology Commission[18ZR1403900] ; Shanghai Science and Technology Commission[20430713600] ; Shanghai Science and Technology Commission[18JC1413800] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001253155700001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/311893]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhao, Yujun; Meng, Xiangjing; Zhu, Di |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res & Small Mol Drug Res Ctr, Shanghai 201203, Peoples R China 2.DP Technol, Beijing 100080, Peoples R China 3.Shandong Acad Pharmaceut Sci, Jinan 250101, Peoples R China 4.Shanghai Jiao Tong Univ, Shanghai 201210, Peoples R China 5.Fudan Univ, Sch Basic Med Sci, Shanghai 201210, Peoples R China 6.Yangtze Delta Pharmaceut Coll, Nantong 226133, Peoples R China 7.Yangtze Delta Drug Adv Res Inst, Nantong 226133, Peoples R China 8.Anhui Univ Chinese Med, Hefei 230012, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhu, Wenhua,Liu, Cuiting,Xi, Kang,et al. 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[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:36. |
| APA | Zhu, Wenhua.,Liu, Cuiting.,Xi, Kang.,Li, Anqi.,Shen, Li-an.,...&Zhu, Di.(2024).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,36. |
| MLA | Zhu, Wenhua,et al."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):36. |
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。