Radioactive ADME Demonstrates ARV-110's High Druggability Despite Low Oral Bioavailability
文献类型：期刊论文
| 作者 | He, Yifei3,4; Zheng, Yuandong4; Zhu, Chenggu2; Lei, Peng4; Yu, Jinghua4; Tang, Chongzhuang1; Chen, Hao3,4; Diao, Xingxing1,3,4 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2024-07-29 |
| 页码 | 15 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.4c01104 |
| 通讯作者 | Chen, Hao(haoc@simm.ac.cn) ; Diao, Xingxing(xxdiao@simm.ac.cn) |
| 英文摘要 | Proteolysis-targeting chimeras (PROTACs) have emerged as potentially effective therapeutic medicines, but their high molecular weight and poor solubility directly impact their oral bioavailability. This work synthesized C-14-labeled bavdegalutamide (ARV-110) as a model compound of PROTACs to evaluate its ADME features. Compared with targeted antitumor drugs, the use of food increased oral bioavailability of ARV-110 in rats from 10.75% to 20.97%, which is still undesirable. However, the therapeutic effect of ARV-110 at a low dose was much better than that of enzalutamide, demonstrating the specific catalytic medicinal properties of PROTACs. Moreover, the specific distribution of ARV-110 in subcutaneous prostate tumors was determined by quantitative whole-body autoradiography (QWBA). Notably, the specificity and activity of PROTACs take precedence over their oral absorption, and high oral bioavailability is not necessary to produce excellent therapeutic effects. This work presents a roadmap for developing future PROTAC medications from a radioactive drug metabolism and pharmacokinetics (DMPK) perspective. |
| WOS关键词 | INDUCED PROTEIN-DEGRADATION ; THALIDOMIDE ; HYDROLYSIS ; STABILITY |
| 资助项目 | National Natural Science Foundation of China[82373938] ; National Natural Science Foundation of China[82104276] ; National Natural Science Foundation of China[82104275] ; National Natural Science Foundation of China[82204585] ; National Natural Science Foundation of China[82071976] ; Key Technologies R&D Program of Guangdong Province[2023B1111030004] ; National Key R&D Program of China[2022YFF1202600] ; Wuxi Beita Pharmatech Co., Ltd. |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001280428700001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/312544]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Chen, Hao; Diao, Xingxing |
| 作者单位 | 1.XenoFinder Co Ltd, Suzhou 215123, Peoples R China 2.Wuxi Beita Pharmatech Co Ltd, Wuxi 214437, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | He, Yifei,Zheng, Yuandong,Zhu, Chenggu,et al. Radioactive ADME Demonstrates ARV-110's High Druggability Despite Low Oral Bioavailability[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:15. |
| APA | He, Yifei.,Zheng, Yuandong.,Zhu, Chenggu.,Lei, Peng.,Yu, Jinghua.,...&Diao, Xingxing.(2024).Radioactive ADME Demonstrates ARV-110's High Druggability Despite Low Oral Bioavailability.JOURNAL OF MEDICINAL CHEMISTRY,15. |
| MLA | He, Yifei,et al."Radioactive ADME Demonstrates ARV-110's High Druggability Despite Low Oral Bioavailability".JOURNAL OF MEDICINAL CHEMISTRY (2024):15. |
入库方式： OAI收割
来源：上海药物研究所
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