Metabolism of KO143, an ABCG2 inhibitor
Abstract
The ATP-binding cassette sub-family G member 2 (ABCG2) plays an important role in modulating drug disposition and endobiotic homeostasis. KO143 is a potent and relatively selective ABCG2 inhibitor. We found that the metabolic stability of KO143 was very poor in human liver microsomes (HLM). Our further studies illustrated that the tert-butyl ester group in KO143 can be rapidly hydrolyzed and removed by carboxylesterase 1. This metabolic pathway was confirmed as a major pathway of KO143 metabolism in both HLM and mice. K1 is an analog of KO143 without the ester group. We found that the metabolic stability of K1 was significantly improved in HLM when compared to KO143. These data suggest that the ester group in KO143 is the major cause of the poor metabolic stability of KO143. The data from this study can be used to guide the development of KO143 analogs with better metabolic properties.
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Ko143 is not suitable for in vivo application due to its instability in the plasma and rapid inactivation in the liver.
“Ko143, unfortunately, is also not suitable for in vivo application due to its instability in the plasma and rapid inactivation in the liver [129,130].”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [130]
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BindingDB Entry 50022334: Metabolism-guided development of Ko143 analogs as ABCG2 inhibitors.
BindingDB (2025) · UC San Diego · doi:10.7270/q2kd23m3
BindingDB (2022) · UC San Diego · doi:10.7270/q2mp56xk
- Authors
- Liu, K., Zhu, J., Huang, Y., Li, C., Lu, J., Sachar, M., Li, S., & Ma, X.
- Affiliations
- University of Pittsburgh (US)
- Henan Provincial People's Hospital (CN)
- Corresponding author
- Ma, Xiaochao
- Venue
- Drug Metabolism and Pharmacokinetics
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 32
- Issue
- 4
- Pages
- 193-200
- ISSN
- 1347-4367 (ISSN-L)
- OpenAlex
- W2594589933
- Cited by
- 39
- References
- 30
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 9 · 2022: 2 · 2021: 3 · 2020: 7 · 2019: 3 · 2018: 4
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Pharmacokinetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Keywords
- Ko143, ABCG2 inhibitors, drug metabolism, metabolic stability, CES1, human liver microsomes, ester groups
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, Heterocyclic Compounds, 4 or More Rings, Humans, Male, Mice, Inbred Strains, Molecular Conformation, Neoplasm Proteins, Tissue Distribution, Mice, Diketopiperazines
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