In vitro and In vivo Drug Metabolism Analysis of BPI-460372-A Covalent TEAD1/3/4 Inhibitor
文献类型：期刊论文
| 作者 | Liu, Xiaoyun1,3; Zhong, Dafang1 ; Tang, Chongzhuang2; Xu, Xiaofeng3; Lan, Hong3; Diao, Xingxing1,2
|
| 刊名 | CURRENT DRUG METABOLISM
 |
| 出版日期 | 2025-02-11 |
| 页码 | 15 |
| 关键词 | Hippo signaling pathway
TEAD inhibitor
covalent inhibitor
BPI-460372
UHPLC-Orbitrap-HRMS
cysteine
|
| ISSN号 | 1389-2002 |
| DOI | 10.2174/0113892002351556250123105344 |
| 通讯作者 | Lan, Hong(hong.lan@bettapharma.com) ; Diao, Xingxing(xxdiao@simm.ac.cn) |
| 英文摘要 | Background BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the transcriptional enhanced associate domain (TEAD) 1/3/4, which is currently in clinical development for the treatment of cancers with Hippo pathway alterations.Objective This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, and in vitro and in vivo metabolic profile of BPI-460372.Methods The CYP phenotyping and metabolic stability were assessed by measuring the depletion of substrate. The metabolic profile in hepatocytes and rat and dog plasma was analyzed using ultra-high-performance liquid chromatography combined with Orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).Results BPI-460372 was mainly metabolized by CYP2D6, CYP3A4, and CYP1A2. BPI-460372 exhibited low clearance in human, monkey, and rat hepatocytes, while moderate clearance in dog and mouse hepatocytes. A total of 10 metabolites were identified in five species of hepatocytes, and no human-unique metabolite was detected. In rat plasma and dog plasma, the primary metabolites were M407 (BPI-460430) and M423 (BPI-460456), respectively. The two metabolites were quantitatively determined in rat and dog plasma in pharmacokinetic and toxicological studies. The major metabolic site was 2-fluoro-acrylamide, and major metabolic pathways in hepatocytes, and rat and dog plasma involved oxidative defluorination, hydration, glutathione (GSH) conjugation, hydrolysis, cysteine conjugation, and N-acetyl cysteine conjugation. beta-lyase pathway contributed to the metabolism of BPI-460372 in rats to a certain degree.Conclusion This study elucidated the metabolism of BPI-460372 and provided a basis for pharmacokinetic and toxicological species selection, human pharmacokinetics prediction, and assessment of clinical co-administration limitations and possible metabolic pathways in humans. |
| WOS关键词 | PHARMACOKINETICS ; AFATINIB |
| 资助项目 | Shanghai Institute of Materia Medica, Chinese Academy of Sciences |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001435616100001 |
| 出版者 | BENTHAM SCIENCE PUBL LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316490]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Lan, Hong; Diao, Xingxing |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201210, Peoples R China 2.XenoFinder Co Ltd, Suzhou 215123, Peoples R China 3.Betta Pharmaceut Co Ltd, 355 Xingzhong Rd, Hangzhou 311100, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liu, Xiaoyun,Zhong, Dafang,Tang, Chongzhuang,et al. In vitro and In vivo Drug Metabolism Analysis of BPI-460372-A Covalent TEAD1/3/4 Inhibitor[J]. CURRENT DRUG METABOLISM,2025:15. |
| APA | Liu, Xiaoyun,Zhong, Dafang,Tang, Chongzhuang,Xu, Xiaofeng,Lan, Hong,&Diao, Xingxing.(2025).In vitro and In vivo Drug Metabolism Analysis of BPI-460372-A Covalent TEAD1/3/4 Inhibitor.CURRENT DRUG METABOLISM,15. |
| MLA | Liu, Xiaoyun,et al."In vitro and In vivo Drug Metabolism Analysis of BPI-460372-A Covalent TEAD1/3/4 Inhibitor".CURRENT DRUG METABOLISM (2025):15. |
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。