In vitro and In vivo Drug Metabolism Analysis of BPI-460372 - A Covalent TEAD1/3/4 Inhibitor

Area of Science:

• Pharmacology
• Drug Metabolism
• Oncology

Background:

• BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor targeting TEAD 1/3/4.
• It is under clinical development for cancers with Hippo pathway alterations.

Purpose of the Study:

• To determine the cytochrome P450 (CYP) phenotyping of BPI-460372.
• To assess its metabolic stability and in vitro/in vivo metabolic profile.

Main Methods:

• CYP phenotyping and metabolic stability assessed via substrate depletion.
• Metabolic profiling in hepatocytes and plasma using UHPLC-Orbitrap-HRMS.

Main Results:

• BPI-460372 primarily metabolized by CYP2D6, CYP3A4, and CYP1A2.
• Low clearance in human, monkey, and rat hepatocytes; moderate in dog and mouse.
• Identified 10 metabolites across species; major pathways include oxidative defluorination, conjugation, and hydrolysis.

Conclusions:

• Elucidated BPI-460372 metabolism, aiding species selection for pharmacokinetic and toxicological studies.
• Provides a basis for predicting human pharmacokinetics and assessing drug-drug interaction risks.