N-Glucuronide Metabolite of Camonsertib

Biosynthesis and identification of an N-Glucuronide Metabolite of Camonsertib

This paper published jointly by scientists at Repare Therapeutics, BioAgilytix and Hypha Discovery describes the synthesis of a prominent human N-glucuronide metabolite of camonsertib by microbial biotransformation, and its subsequent identification by NMR spectroscopy.

Abstract

Camonsertib is a novel ATR kinase inhibitor in clinical development for advanced cancers targeting sensitizing mutations. This article describes the identification and biosynthesis of an N-glucuronide metabolite of camonsertib.

This metabolite was first observed in human hepatocyte incubations and was subsequently isolated to determine the structure, evaluate its stability as part of bioanalytical method development and for use as a standard for estimating its concentration in phase I samples.

The N-glucuronide was scaled-up using a purified bacterial culture preparation and was subsequently isolated using preparative chromatography. The bacterial culture generated sufficient material of the glucuronide to allow for one- and two-dimensional ¹H and ¹³C NMR structural elucidation and further bioanalytical characterization. The nuclear Overhauser effect data combined with the gradient heteronuclear multiple bond correlation experiment and molecular modeling, strongly suggests that the point of attachment of the glucuronide results in the formation of (2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-(5-(4-((1R,3r,5S)-3-hydroxy-8-oxabicyclo[3.2.1]octan-3-yl)-6-((R)-3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-1H-pyrazol-1-yl)tetrahydro-2H-pyran-2-carboxylic acid.