Role of ABCG2 / BCRP in multidrug resistance and development in design of its inhibitors
ABCG2/BCRP is a second member of the ATP binding cassette transporter protein subfamily G which has been shown to be involved the multidrug resistance in cancer and failure of the therapy.
Multidrug resistance (MDR) is one of the main cause of failure of chemotherapy used for the treatment of different cancers. Along with several other factors, overexpression of ATP binding cassette (ABC) transporter proteins have been shown to be involved in emergence of MDR. BCRP/ABCG2 is a second member of the ABC proteins subfamily G and is encoded by the ABCG2 gene. It is an efflux protein and has been shown to be overexpressed in tumors, leading to extrusion of drug and hence lower accumulation of drug compounds and eventually causing drug resistance. One of the strategies to overcome drug resistance due to overexpression of ABCG2 is the development of potent and selective inhibitors of ABCG2.
ABCG2 has been shown to confer resistance to chemically unrelated anticancer drugs such as mitoxantrone, topotecan, irinotecan and flavopiridol. ABCG2 overexpression has been identified in a variety of solid tumors, acute myelogenous leukemia and chronic myeloid leukemia, which has often been correlated to poor therapeutic outcome. Due to the presence of ABCG2 in the intestine and various protection barriers, it has also been shown to influence drug absorption, distribution, metabolism and elimination and bioavailability. These findings make ABCG2 an interesting target to overcome MDR and also to improve the pharmacokinetics of the drugs that are substrates of ABCG2.
Since the discovery of ABCG2 lots of work has been carried out to identify potent, selective and non-toxic inhibitors of the ABCG2. Until now several scaffolds of inhibitors have been identified either through screening of naturally occurring compounds or drug compounds already known for other targets. These include chalcones, naturally occurring flavonoids and their derivatives. Recently quinazolines were found to be potent inhibitors of ABCG2. The structure activity and structure toxicity relationship studies carried out in recent works would be of great help to design of safe inhibitors of ABCG2.
In the following review we have discussed progress in the design of chalcones, flavones and quinazolines as selective and potent inhibitors of ABCG2/BCRP: