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New, highly potent and non-toxic, chromone inhibitors of the human breast cancer resistance protein ABCG2
- Source :
- European journal of medicinal chemistry. 122
- Publication Year :
- 2016
-
Abstract
- Breast cancer resistance protein (BCRP/ABCG2) is one of the major transporters involved in the efflux of anticancer compounds, contributing to multidrug resistance (MDR). Inhibition of ABCG2-mediated transport is then considered a promising strategy for overcoming MDR in tumors. We recently identified a chromone derivative, namely MBL-II-141 as a selective ABCG2 inhibitor, with relevant in vivo activity. Here, we report the pharmacomodulation of MBL-II-141, with the aim of identifying key pharmacophoric elements to design more potent selective and non-toxic inhibitors. Through rational structural modifications of MBL-II-141, using simple and affordable chemistry, we obtained highly active and easily-made inhibitors of ABCG2. Among the investigated compounds, derivative 4a, was found to be 3-fold more potent than MBL-II-141. It was similarly efficient as the reference inhibitor Ko143 but with the advantage of a lower intrinsic cytotoxicity, and therefore constitutes the best ABCG2 inhibitor ever reported displaying a very high therapeutic ratio.
- Subjects :
- 0301 basic medicine
Cancer resistance
Abcg2
Breast Neoplasms
Pharmacology
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
0302 clinical medicine
Therapeutic index
Drug Discovery
ATP Binding Cassette Transporter, Subfamily G, Member 2
Humans
Cytotoxicity
biology
Chemistry
Organic Chemistry
Transporter
General Medicine
Multiple drug resistance
030104 developmental biology
HEK293 Cells
Chromones
030220 oncology & carcinogenesis
Drug Design
Chromone
biology.protein
Efflux
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 122
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....f66206ed36a4f268763918ee14e39eb9