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In-vitro metabolism of LXY18, an orally available, potent blocker of AURKB relocation in mitosis.
- Source :
-
Journal of Pharmaceutical & Biomedical Analysis . Aug2023, Vol. 232, pN.PAG-N.PAG. 1p. - Publication Year :
- 2023
-
Abstract
- This study investigated the metabolism of LXY18, a quinolone-based compound that suppresses tumorigenesis by blocking AURKB localization. Metabolite profiling of LXY18 in liver microsomes from six species and human S9 fractions revealed that LXY18 undergoes various conserved metabolic reactions, such as N-hydroxylation, N-oxygenation, O-dealkylation, and hydrolysis, resulting in ten metabolites. These metabolites were produced through a combination of CYP450 enzymes, and non-CYP450 enzymes including CES1, and AO. Two metabolites, M1 and M2 were authenticated by chemically synthesized standards. M1 was the hydrolyzed product catalyzed by CES1 whereas M2 was a mono-N-oxidative derivative catalyzed by a CYP450 enzyme. AO was identified as the enzyme responsible for the formation of M3 with the help of AO-specific inhibitors and LXY18 analogs, 5b and 5c. M1 was the intermediate of LXY18 to produce M7, M8, M9, and M10. LXY18 potently inhibited 2C19 with an IC 50 of 290 nM but had a negligible impact on the other CYP450s, indicating a low risk of drug-drug interaction. Altogether, the study provides valuable insights into the metabolic process of LXY18 and its suitability as a drug candidate. The data generated serves as a significant reference point for conducting further safety assessments and optimizing drug development. • Interspecies metabolite profiling LXY18 shows conserved metabolic pathways. • Ten metabolites produced through CYP enzymes, CES1, and AO. • CES1 produces the hydrolyzed product, M1. • Mono-oxidative metabolite M3 by using AO-specific inhibitors and LXY18 analogs. • LXY18 potently inhibits 2C19 but has minimal effect on other CYPs. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 07317085
- Volume :
- 232
- Database :
- Academic Search Index
- Journal :
- Journal of Pharmaceutical & Biomedical Analysis
- Publication Type :
- Academic Journal
- Accession number :
- 163944906
- Full Text :
- https://doi.org/10.1016/j.jpba.2023.115415