Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma
文献类型：期刊论文
| 作者 | Chang, Qi1; Li, Jiayi2,3,4; Deng, Yue2,4; Zhou, Ruilin5; Wang, Bingwei5; Wang, Yujie1; Zhang, Mingming1; Huang, Xun2,3,6 ; Li, Yingxia1,7
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2024-02-05 |
| 卷号 | 67期号:4页码:2466-2486 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.3c01468 |
| 通讯作者 | Huang, Xun(xhuang@lglab.ac.cn) ; Li, Yingxia(liyx417@fudan.edu.cn) |
| 英文摘要 | Adenoviral E1A binding protein 300 kDa (p300) and its closely related paralog CREB binding protein (CBP) are promising therapeutic targets for human cancer. Here, we report the first discovery of novel potent small-molecule PROTAC degraders of p300/CBP against hepatocellular carcinoma (HCC), one of the most common solid tumors. Based upon the clinical p300/CBP bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize the linker to generate a series of PROTACs, culminating in the identification of QC-182. This compound effectively induces p300/CBP degradation in the SK-HEP-1 HCC cells in a dose-, time-, and ubiquitin-proteasome system-dependent manner. QC-182 significantly downregulates p300/CBP-associated transcriptome in HCC cells, leading to more potent cell growth inhibition compared to the parental inhibitors and the reported degrader dCBP-1. Notably, QC-182 potently depletes p300/CBP proteins in mouse SK-HEP-1 xenograft tumor tissue. QC-182 is a promising lead compound toward the development of p300/CBP-targeted HCC therapy. |
| WOS关键词 | CBP/P300 ; CBP ; PROTEIN ; PROLIFERATION ; ACETYLATION ; DEGRADATION ; INHIBITORS ; TARGETS ; FAMILY ; TOOLS |
| 资助项目 | National Natural Science Foundation of China[U1906212] ; National Natural Science Foundation of China[22XD1425300] ; Program of Shanghai Subject Chief Scientist |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001163336200001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309578]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Huang, Xun; Li, Yingxia |
| 作者单位 | 1.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Nanjing Univ Chinese Med, Sch Med & Holist Integrat Med, Nanjing 210023, Peoples R China 6.Lin Gang Lab, Shanghai 200210, Peoples R China 7.Fudan Univ, Huashan Hosp, Shanghai Med Coll, Natl Med Ctr Infect Dis,DeptInfect Dis,Shanghai Ke, Shanghai 200040, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chang, Qi,Li, Jiayi,Deng, Yue,et al. Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(4):2466-2486. |
| APA | Chang, Qi.,Li, Jiayi.,Deng, Yue.,Zhou, Ruilin.,Wang, Bingwei.,...&Li, Yingxia.(2024).Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma.JOURNAL OF MEDICINAL CHEMISTRY,67(4),2466-2486. |
| MLA | Chang, Qi,et al."Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma".JOURNAL OF MEDICINAL CHEMISTRY 67.4(2024):2466-2486. |
入库方式： OAI收割
来源：上海药物研究所
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