Liu Xiaoyun, Zhong Dafang, Tang Chong Zhuang, Xu Xiaofeng, Lan Hong, Diao Xingxing
Betta Pharmaceuticals Co., Ltd, Hangzhou, 311100, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201210, China.
Curr Drug Metab. 2025 Feb 11;25(10):754-68. doi: 10.2174/0113892002351556250123105344.
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.
This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, and in vitro and in vivo metabolic profile of BPI-460372.
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).
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. β-lyase pathway contributed to the metabolism of BPI-460372 in rats to a certain degree.
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.
BPI-460372是一种口服可用的、共价的、不可逆的转录增强关联结构域（TEAD）1/3/4小分子抑制剂，目前正处于临床开发阶段，用于治疗具有Hippo通路改变的癌症。
本研究旨在确定BPI-460372的细胞色素P450（CYP）表型、代谢稳定性以及体外和体内代谢谱。
通过测量底物消耗来评估CYP表型和代谢稳定性。使用超高效液相色谱结合Orbitrap串联质谱（UHPLC-Orbitrap-HRMS）分析肝细胞以及大鼠和犬血浆中的代谢谱。
BPI-460372主要由CYP2D6、CYP3A4和CYP1A2代谢。BPI-460372在人、猴和大鼠肝细胞中清除率较低，而在犬和小鼠肝细胞中清除率中等。在五种肝细胞中总共鉴定出10种代谢物，未检测到人类特有的代谢物。在大鼠血浆和犬血浆中，主要代谢物分别为M407（BPI-460430）和M423（BPI-460456）。在药代动力学和毒理学研究中对大鼠和犬血浆中的这两种代谢物进行了定量测定。主要代谢位点是2-氟丙烯酰胺，肝细胞以及大鼠和犬血浆中的主要代谢途径包括氧化脱氟、水合、谷胱甘肽（GSH）结合、水解、半胱氨酸结合和N-乙酰半胱氨酸结合。β-裂合酶途径在一定程度上参与了BPI-460372在大鼠体内的代谢。
本研究阐明了BPI-460372的代谢情况，为药代动力学和毒理学实验动物的选择、人体药代动力学预测以及评估临床联合用药限制和人体可能的代谢途径提供了依据。
