Mitoxantrone accumulation studies showed that the three compounds were more potent than FTC and that Ko143 was twice as potent as GF120918. in the literature used for the prediction of ABCG2 substrates and inhibitors. white protein, and two sterol transporters, among others (4). ABCG2 shares limited amino acid sequence similarity with ABCB1 and ABCC1 but has 29.3% identity with the human homolog of white protein ABCG1. The difference between ABCG2 and other ABC efflux transporters is evident by examining the structure of the protein. ABCG2 is composed of only 655 amino acids that make up its single nucleotide binding domain and six transmembrane domains, while many other ABC transporters are comprised of two nucleotide binding and 12 transmembrane domains. It is known that eukaryotic ABC transporters require at least two nucleotide binding and 12 transmembrane domains for transporter activity; therefore, ABCG2 is considered a half-transporter and functions by forming homodimers (4). Molecular mechanisms controlling ABCG2 expression have not been fully identified, but recent studies suggest regulation through sex hormones, hypoxia, peroxisome proliferator activated receptor Vanoxerine 2HCl (GBR-12909) (PPAR), or the aryl-hydrocarbon (Ahr) receptor. The sex hormones estradiol, progesterone, and testosterone affect ABCG2 regulation at the transcriptional level, but the data are controversial, particularly concerning cell-type-dependent estradiol effects (5). Additionally, histone modification was shown to be important in regulating ABCG2 in resistant cells. ABCG2 induction has also been noted following administration of histone deacetylase inhibitor romidepsin, though the effects are cell type specific (6). Regulation of ABCG2 has been described in normal cells to date, with little known regarding changes in regulation in cancer cells. Tissue Distribution and Cellular Localization ABCG2 tissue distribution is ubiquitous, Vanoxerine 2HCl (GBR-12909) with high mRNA expression in the placenta and lower levels in the brain, prostate, intestine, testis, ovary, and liver. ABCG2 expression in cancer cells has been linked to the multidrug resistance phenomenon, but the data are controversial. ABCG2 expression in breast cancer has been extensively studied, and the consensus is that expression levels are relatively low (5). In polarized cells, ABCG2 is located on the apical membrane and can limit the entry of xenobiotics across the small intestine Vanoxerine 2HCl (GBR-12909) or the bloodCplacental barrier (4). Substrates and Inhibitors ABCG2 transports a variety of substrates, some shared with ABCB1 and ABCC1 but some are ABCG2 specific. ABCG2 has been shown to transport chemotherapy agents, anti-virals, HMG-CoA reductase inhibitors, carcinogens, fluorescent compounds like rhodamine 123 and Hoechst 33342, flavonoids, phase II metabolites including sulfate and glucuronide conjugates, antibiotics, and many others (4). ABCG2 substrates include mitoxantrone, topotecan, SN-38, and flavopiridol among others. ABCG2 transport, unlike those of ABCC1 and ABCC2, is not dependent on intracellular GSH concentration. ABCG2 inhibitors include some ABCB1 inhibitors such as elacridar (GF120918), cyclosporine A, and tariquidar (XR9576). Other inhibitors include estrone and 17-estradiol and flavonoids quercetin, biochanin A, and genistein. Since many flavonoids are found in the diet, these compounds can significantly affect the pharmacokinetics and pharmacodynamics of ABCG2 substrates and also lead to dietCdrug interactions (7). Function ABCG2 plays an important role in drug absorption, distribution, and elimination and in drug efficacy. Based on the tissue distribution of ABCG2, its presumed function includes protecting the body from xenobiotics through its role at the bloodCbrain, bloodCtestis, maternalCfetal barriers and in efflux of xenobiotics at the small intestine brush border and liver canalicular membranes. BCL2L8 ABCG2 can play a role in multidrug resistance, and many inhibitors have been synthesized to overcome this effect. There is also considerable interest in identifying ABCG2 substrates because ABCG2 substrates can have poor oral bioavailability, extensive first pass Vanoxerine 2HCl (GBR-12909) elimination via the biliary route, and poor efficacy as cancer therapeutic agents. Supporting evidence has been reported by Jonker models to predict ABCG2 substrates and inhibitors and to determine if any structural features are necessary for transport or inhibition of ABCG2. SAR AND QSAR OF ABCG2 INHIBITORS modeling is.