Advertisement

The AAPS Journal

, 11:541 | Cite as

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

  • Yash A. Gandhi
  • Marilyn E. MorrisEmail author
Review Article Theme: Structure-Activity relationships for ABC Transporters

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.

Key words

ABC transporter ABCG2 breast cancer resistance protein quantitative structure–activity relationships structure–activity relationships 

Notes

Acknowledgements

Support was provided by the Susan G. Komen Foundation BCTR0601385 and from Pfizer Inc.

References

  1. 1.
    Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A. 1998;95:15665–70.PubMedCrossRefGoogle Scholar
  2. 2.
    Allikmets R, Schriml LM, Hutchinson A, Romano-Spica V, Dean M. A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res. 1998;58:5337–9.PubMedGoogle Scholar
  3. 3.
    Miyake K, Mickley L, Litman T, Zhan Z, Robey R, Cristensen B, et al. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res. 1999;59:8–13.PubMedGoogle Scholar
  4. 4.
    Robey R, Polgar O, Deeken J, To KK, Bates SE. Breast cancer resistance protein. In: You G, Morris ME, editors. Drug transporters: molecular characterization and role in drug disposition. Hoboken: Wiley; 2007. p. 319–58.Google Scholar
  5. 5.
    Robey RW, To KK, Polgar O, Dohse M, Fetsch P, Dean M, et al. ABCG2: a perspective. Adv Drug Deliv Rev. 2009;61:3–13.PubMedCrossRefGoogle Scholar
  6. 6.
    To KK, Polgar O, Huff LM, Morisaki K, Bates SE. Histone modifications at the ABCG2 promoter following treatment with histone deacetylase inhibitor mirror those in multidrug-resistant cells. Mol Cancer Res. 2008;6:151–64.PubMedCrossRefGoogle Scholar
  7. 7.
    Zhang S, Yang X, Morris ME. Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol Pharmacol. 2004;65:1208–16.PubMedCrossRefGoogle Scholar
  8. 8.
    Jonker JW, Smit JW, Brinkhuis RF, Maliepaard M, Beijnen JH, Schellens JH, et al. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst. 2000;92:1651–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Mager DE, Jusko WJ. Quantitative structure-pharmacokinetic/pharmacodynamic relationships of corticosteroids in man. J Pharm Sci. 2002;91:2441–51.PubMedCrossRefGoogle Scholar
  10. 10.
    Mager DE. Quantitative structure-pharmacokinetic/pharmacodynamic relationships. Adv Drug Deliv Rev. 2006;58:1326–56.PubMedCrossRefGoogle Scholar
  11. 11.
    Nicolle E, Boumendjel A, Macalou S, Genoux E, Ahmed-Belkacem A, Carrupt PA, et al. QSAR analysis and molecular modeling of ABCG2-specific inhibitors. Adv Drug Deliv Rev. 2009;61:34–46.PubMedCrossRefGoogle Scholar
  12. 12.
    Minderman H, Brooks T, O’Loughlin KL, Ojima I, Bernacki RJ, Baer MR. Multidrug resistance (MDR) modulation by the taxane derivatives IDN-5109 and tRA 96023: effects on P-glycoprotein (Pgp)-, multidrug resistance protein (MRP-1)-, and breast cancer resistance protein (BCRP)-mediated drug transport. Proc Am Assoc Cancer Res. 2002;43:950.Google Scholar
  13. 13.
    Brooks TA, Kennedy DR, Gruol DJ, Ojima I, Baer MR, Bernacki RJ. Structure-activity analysis of taxane-based broad-spectrum multidrug resistance modulators. Anticancer Res. 2004;24:409–15.PubMedGoogle Scholar
  14. 14.
    Ecker G, Huber M, Schmid D, Chiba P. The importance of a nitrogen atom in modulators of multidrug resistance. Mol Pharmacol. 1999;56:791–6.PubMedGoogle Scholar
  15. 15.
    Ehrlich P. Present status of chemotherapy. Ber Dtsch Chem Ges. 1909;42:17–47.CrossRefGoogle Scholar
  16. 16.
    Cramer J, Kopp S, Bates SE, Chiba P, Ecker GF. Multispecificity of drug transporters: probing inhibitor selectivity for the human drug efflux transporters ABCB1 and ABCG2. ChemMedChem. 2007;2:1783–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Havsteen BH. The biochemistry and medical significance of the flavonoids. Pharmacol Ther. 2002;96:67–202.PubMedCrossRefGoogle Scholar
  18. 18.
    Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. 2000;52:673–751.PubMedGoogle Scholar
  19. 19.
    Zhang S, Yang X, Coburn RA, Morris ME. Structure activity relationships and quantitative structure activity relationships for the flavonoid-mediated inhibition of breast cancer resistance protein. Biochem Pharmacol. 2005;70:627–39.PubMedCrossRefGoogle Scholar
  20. 20.
    Ahmed-Belkacem A, Pozza A, Munoz-Martinez F, Bates SE, Castanys S, Gamarro F, et al. Flavonoid structure-activity studies identify 6-prenylchrysin and tectochrysin as potent and specific inhibitors of breast cancer resistance protein ABCG2. Cancer Res. 2005;65:4852–60.PubMedCrossRefGoogle Scholar
  21. 21.
    Boumendjel A, Macalou S, Ahmed-Belkacem A, Blanc M, Di Pietro A. Acridone derivatives: design, synthesis, and inhibition of breast cancer resistance protein ABCG2. Bioorg Med Chem. 2007;15:2892–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Imai Y, Tsukahara S, Ishikawa E, Tsuruo T, Sugimoto Y. Estrone and 17beta-estradiol reverse breast cancer resistance protein-mediated multidrug resistance. Jpn J Cancer Res. 2002;93:231–5.PubMedGoogle Scholar
  23. 23.
    Imai Y, Tsukahara S, Asada S, Sugimoto Y. Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance. Cancer Res. 2004;64:4346–52.PubMedCrossRefGoogle Scholar
  24. 24.
    Katayama K, Masuyama K, Yoshioka S, Hasegawa H, Mitsuhashi J, Sugimoto Y. Flavonoids inhibit breast cancer resistance protein-mediated drug resistance: transporter specificity and structure-activity relationship. Cancer Chemother Pharmacol. 2007;60:789–97.PubMedCrossRefGoogle Scholar
  25. 25.
    Ahmed-Belkacem A, Macalou S, Borrelli F, Capasso R, Fattorusso E, Taglialatela-Scafati O, et al. Nonprenylated rotenoids, a new class of potent breast cancer resistance protein inhibitors. J Med Chem. 2007;50:1933–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Sugimoto Y, Tsukahara S, Imai Y, Sugimoto Y, Ueda K, Tsuruo T. Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists. Mol Cancer Ther. 2003;2:105–12.PubMedGoogle Scholar
  27. 27.
    Pick A, Muller H, Wiese M. Structure-activity relationships of new inhibitors of breast cancer resistance protein (ABCG2). Bioorg Med Chem. 2008;16:8224–36.PubMedCrossRefGoogle Scholar
  28. 28.
    Cui C, Kakeya H, Osada H. Novel mammalian cell cycle inhibitors, cyclotryprostatins A-D, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron. 1997;53:59–72.CrossRefGoogle Scholar
  29. 29.
    van Loevezijn A, Allen JD, Schinkel AH, Koomen GJ. Inhibition of BCRP-mediated drug efflux by fumitremorgin-type indolyl diketopiperazines. Bioorg Med Chem Lett. 2001;11:29–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Allen JD, van Loevezijn A, Lakhai JM, van der Valk M, van Tellingen O, Reid G, et al. Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Mol Cancer Ther. 2002;1:417–25.PubMedGoogle Scholar
  31. 31.
    Nurse PM. Nobel Lecture. Cyclin dependent kinases and cell cycle control. Biosci Rep. 2002;22:487–99.PubMedCrossRefGoogle Scholar
  32. 32.
    Saito H, Hirano H, Nakagawa H, Fukami T, Oosumi K, Murakami K, et al. A new strategy of high-speed screening and quantitative structure-activity relationship analysis to evaluate human ATP-binding cassette transporter ABCG2-drug interactions. J Pharmacol Exp Ther. 2006;317:1114–24.PubMedCrossRefGoogle Scholar
  33. 33.
    An R, Hagiya Y, Tamura A, Li S, Saito H, Tokushima D, et al. Cellular phototoxicity evoked through the inhibition of human ABC transporter ABCG2 by cyclin-dependent kinase inhibitors in vitro. Pharm Res. 2009;26:449–58.PubMedCrossRefGoogle Scholar
  34. 34.
    Matsson P, Englund G, Ahlin G, Bergstrom CA, Norinder U, Artursson P. A global drug inhibition pattern for the human ATP-binding cassette transporter breast cancer resistance protein (ABCG2). J Pharmacol Exp Ther. 2007;323:19–30.PubMedCrossRefGoogle Scholar
  35. 35.
    Chang C, Ekins S, Bahadduri P, Swaan PW. Pharmacophore-based discovery of ligands for drug transporters. Adv Drug Deliv Rev. 2006;58:1431–50.PubMedCrossRefGoogle Scholar
  36. 36.
    Xu Y, Villalona-Calero MA. Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol. 2002;13:1841–51.PubMedCrossRefGoogle Scholar
  37. 37.
    Yoshikawa M, Ikegami Y, Hayasaka S, Ishii K, Ito A, Sano K, et al. Novel camptothecin analogues that circumvent ABCG2-associated drug resistance in human tumor cells. Int J Cancer. 2004;110:921–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Nakagawa H, Saito H, Ikegami Y, Aida-Hyugaji S, Sawada S, Ishikawa T. Molecular modeling of new camptothecin analogues to circumvent ABCG2-mediated drug resistance in cancer. Cancer Lett. 2006;234:81–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhou XF, Shao Q, Coburn RA, Morris ME. Quantitative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 1, 4-dihydropyridines and pyridines as multidrug resistance modulators. Pharm Res. 2005;22:1989–96.PubMedCrossRefGoogle Scholar
  40. 40.
    Gombar VK, Polli JW, Humphreys JE, Wring SA, Serabjit-Singh CS. Predicting P-glycoprotein substrates by a quantitative structure-activity relationship model. J Pharm Sci. 2004;93:957–68.PubMedCrossRefGoogle Scholar
  41. 41.
    Ha SN, Hochman J, Sheridan RP. Mini review on molecular modeling of P-glycoprotein (Pgp). Curr Top Med Chem. 2007;7:1525–9.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesUniversity at Buffalo, State University of New YorkAmherstUSA

Personalised recommendations