Structure-activity relationships and quantitative structure-activity relationships for breast cancer resistance protein (ABCG2)

Abstract

Breast cancer resistance protein (ABCG2), the newest ABC transporter, was discovered independently by three groups in the late 1990s. ABCG2 is widely distributed in the body with expression in the brain, intestine, and liver, among others. ABCG2 plays an important role by effluxing drugs at the blood-brain, blood-testis, and maternal-fetal barriers and in the efflux of xenobiotics at the small intestine and kidney proximal tubule brush border and liver canalicular membranes. ABCG2 transports a wide variety of substrates including HMG-CoA reductase inhibitors, antibiotics, and many anticancer agents and is one contributor to multidrug resistance in cancer cells. Quantitative structure-activity relationship (QSAR) models and structure-activity relationships (SARs) are often employed to predict ABCG2 substrates and inhibitors prior to in vitro and in vivo studies. QSAR models correlate in vivo biological activity to physicochemical properties of compounds while SARs attempt to explain chemical moieties or structural features that contribute to or are detrimental to the biological activity. Most ABCG2 datasets available for in silico modeling are comprised of congeneric series of compounds; the results from one series usually cannot be applied to another series of compounds. This review will focus on in silico models in the literature used for the prediction of ABCG2 substrates and inhibitors.

Fig. 1

Chemical structure of paclitaxel analogues with substitutions at position 1, 2, 3, and 4 (Fig. 1a). The most potent inhibitor selected using structure–activity relationships (Fig. 1b) (13)

Fig. 2

Chemical structure of propafenone analogues with two substituent groups R₁ and R₂ (16)

Fig. 3

Representative structures of the six different classes of flavonoids (19)

Fig. 4

Summary of structure–activity relationships for apigenin analogues. Thin arrows show unfavorable substitutions, while thick arrows show favorable substitutions (20). Reproduced with permission with American Association for Cancer Research in the format journal via copyright clearance center. Copyright 2005 by American Association for Cancer Research

Fig. 5

Structural analogues of tectochrysin with substitutions at positions R₁, R₂, and R₃ and of GF120918 with substitutions at position R and Y (21)

Fig. 6

Rotenoid derivatives isolated from the plant Boerhaavia diffusa with substitutions at positions 3, 4, 6, 8, 9, and 10 and the presence or absence of a double bond between positions 6a and 12a (25)

Fig. 7

Structure of tamoxifen analogues designed to inhibit ABCG2 (26)

Fig. 8

Template 1 derived from anthranilamide and template two based on the tetrahydroisoquinoline-ethyl-phenyl-amide backbone (27)

Fig. 9

Fumitreomorgin C analogues with six possible substituents at R₁ (a–f) and seven possible substitutents at R₂ (–7) (29)

Fig. 10

Chemical structure of SN-38 analogues with substitutions at position X and Y (37). Reprinted with permission of John Wiley & Sons, Inc from Novel camptothecin analogues that circumvent ABCG2-associated drug resistance in human tumor cells, Vol. 110, No. 6, 2004, pp 921–927. Copyright 2009