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2000
Volume 25, Issue 10
  • ISSN: 1389-2002
  • E-ISSN: 1875-5453
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Abstract

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.

Objectives

This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, and and 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 -acetyl cysteine conjugation. -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.

© 2024 The Author(s).
© 2024 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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In vitro and In Vivo Drug Metabolism Analysis of BPI-460372 - A Covalent TEAD1/3/4 Inhibitor
Current Drug Metabolism 25, 754 (2024); https://doi.org/10.2174/0113892002351556250123105344
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  • Article Type:     Research Article
Keyword(s): BPI-460372; covalent inhibitor; cysteine S-conjugate β-lyase; Hippo signaling pathway; TEAD inhibitor; UHPLC-Orbitrap-HRMS

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