A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)

Abstract

In this article, we explore the entire structural space of registered drugs to obtain a global model for the inhibition of the drug efflux transporter breast cancer resistance protein (BCRP; ABCG2). For this purpose, the inhibitory effect of 123 structurally diverse drugs and drug-like compounds on mitoxantrone efflux was studied in Saos-2 cells transfected with human wild-type (Arg482) BCRP. The search for BCRP inhibitors throughout the drug-like chemical space resulted in the identification of 29 previously unknown inhibitors. The frequency of BCRP inhibition was 3 times higher for compounds reported to interact with other ATP-binding cassette (ABC) transporters than for compounds without reported ABC transporter affinity.An easily interpreted computational model capable of discriminating inhibitors from noninhibitors using only two molecular descriptors, octanol-water partition coefficient at pH 7.4 and molecular polarizability, was constructed. The discriminating power of this two-descriptor model was 93% for the training set and 79% for the test set, respectively. The results were supported by a global pharmacophore model and are in agreement with a two-step mechanism for the inhibition of BCRP, where both the drug's capacity to insert into the cell membrane and to interact with the inhibitory binding site of the transporter are important.The ATP-binding cassette (ABC) transporter breast cancer resistance protein (BCRP; ABCG2) has received much attention for its role in resistance to various cytotoxic agents (Doyle et al., 1998;Krishnamurthy and Schuetz, 2006) and has recently been shown to also influence the disposition of structurally unrelated drugs from other therapeutic classes (Gupta et al., 2004;Jonker et al., 2005;Zhang et al., 2005). BCRP is expressed in many tissue barriers throughout the body, including the intestine, the blood-brain barrier, the blood-placenta barrier, and the liver canalicular membrane (Maliepaard et al., 2001;Fetsch et al., 2006). A picture is emerging that, similar to the most well studied ABC transporter, P-glycoprotein (ABCB1), BCRP interacts with a wide variety of compounds, and it is one of the major ABC transporters affecting drug disposition throughout the body. The key role of BCRP in drug disposition was recently exemplified by a 111 times higher systemic exposure to the antiinflammatory drug sulfasalazine after oral administration to Bcrp1-knockout mice compared with wild-type mice (Zaher et al., 2006). Furthermore, the human oral bioavailability of the BCRP substrate topotecan was more than doubled after coadministration with the potent inhibitor GF120918 (Elacridar) (Kruijtzer et al., 2002), highlighting the risk of significantly altered drug exposure due to inhibition of BCRP. It would therefore be of great interest to develop models that can predict drug-mediated BCRP inhibition, but so far, studies have been limited to structurally homologous series of compounds (Gupta et al., 2004), and the only published computational model was not validated with an ex...

Structure–Activity Relationships and Quantitative Structure–Activity Relationships for Breast Cancer Resistance Protein (ABCG2)

“…A pharmacophore model was generated using 28 inhibitors in the training set. The pharmacophore was described by two hydrophobic features and one hydrogen bond acceptor, confirming the QSAR results (34).…”

“…Lipophilicity, expressed as log D 7.4 was present in another model to predict ABCG2 inhibitors. The authors suggest a log D cutoff of 0.5, above which there is an increased likelihood of a compound-inhibiting ABCG2 (34). Though lipophilicity has been shown to be a good predictor of ABCG2 inhibition in some studies, other investigators have not found this descriptor to be significant (16,27).…”

“…One common structural descriptor among the SARs and QSAR models is lipophilicity. Lipophilicity, calculated as either log P or log D, has been shown to be a predictor of inhibition of ABCG2 by a few groups (19,29,34). In our laboratory, we have derived a QSAR model to describe the pEC 50 (-log EC 50 ) values of ABCG2 inhibitors using 19 flavonoids in the training set.…”

Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability

“…Several attempts were made to establish SAR for BCRP interaction, however, many analysis methods were based on the datasets of inhibitors Matsson et al 2007;Matsson et al 2009;Nicolle et al 2009). Yoshikawa et al studied BCRP substrate specificity of 14 camptothecin (CPT) analogues, and noted that CPT analogues that showed ATP-dependent transport in BCRPoverexpressing membrane vesicles possess one -hydroxy or -amino group (Yoshikawa et al 2004).…”

Módosított peptidek szintézise

“…Az utóbbi években számos publikáció született amelyek tárgyát ABCG2 inhibitorok azonosítása képezete. [30,31] …”