ABCMdb

PMID: 19135106

Nicolle E, Boumendjel A, Macalou S, Genoux E, Ahmed-Belkacem A, Carrupt PA, Di Pietro A
QSAR analysis and molecular modeling of ABCG2-specific inhibitors.
Adv Drug Deliv Rev. 2009 Jan 31;61(1):34-46. Epub 2008 Dec 16., 2009-01-31 [PubMed]

Sentences

No. Mutations Sentence Comment

1136 ABCG2 p.Arg482Thr Interestingly, the R482T/G hot-spot mutation, frequently observed in cell cultures selected at high concentration of drugs [55], has been found to be a gain-of-function for drug efflux by extending the transport to anthracyclins and bisantrene [56] as well as to rhodamine 123 [54], an exception being methotrexate which is no longer transported. Login to comment 1137 ABCG2 p.Arg482Thr Direct ligand interactions with purified ABCG2 have shown that the R482T mutation does not modify the binding affinity for a given substrate whether it is transported or not (methotrexate still binds), suggesting that arginine-482, assumed to be located at the inner edge of the third membrane span, is involved in substrate transport, not in binding [57]. Login to comment 1220 ABCG2 p.Arg482Thr 2.1.1. Cellular-based assays Whole cells, either transfected or drug-selected, are mainly used by flow cytometry for studying small series of inhibitors for their ability to induce intracellular accumulation of fluorescent drugs such as mitoxantrone, pheophorbide A, BODIPY-prazosin, LysoTracker, topotecan or Hoechst 33342, and also rhodamine 123 and doxorubicin with the R482T/G mutant [109]. Login to comment 1252 ABCG2 p.Arg482Gly In addition, the effects of the hotspot mutation R482G/T, which are well known to change the pattern of transported substrates, have not been systematically characterized for the inhibitors. Login to comment 1293 ABCG2 p.Arg482Thr Interestingly, the R482T hotspot mutation altered the positive impact of prenylation on the inhibitory potency, tectochrysin being then the best compound with an IC50 of 1.9 μM. The relatively low toxicity of tectochrysin and 6-prenylchrysin and efficient sensitization of cell growth to mitoxantrone made these compounds promising for future potential use in clinical trials. Login to comment