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. β-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.