156
Views
12
CrossRef citations to date
0
Altmetric
Review

Recent advances in computational design of potent aromatase inhibitors: open-eye on endocrine-resistant breast cancers

, &
Pages 1065-1076 | Received 13 May 2019, Accepted 17 Jul 2019, Published online: 24 Jul 2019

References

  • Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO International consensus guidelines for advanced breast cancer (ABC 3). Ann Oncol. 2017 Jan 1;28(1):16–33.
  • Simpson ER, Mahendroo MS, Means GD, et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev. 1994 Jun;15(3):342–355.
  • Spinello A, Ritacco I, Magistrato A. The catalytic mechanism of steroidogenic cytochromes P450 from all-atom simulations: entwinement with membrane environment, redox partners, and post-transcriptional regulation. Catalysts. 2019;9(1):81.
  • Yoshimoto FK, Guengerich FP. Mechanism of the third oxidative step in the conversion of androgens to estrogens by cytochrome P450 19A1 steroid aromatase. J Am Chem Soc. 2014 Oct 22; 136(42):15016–15025.
  • Mak PJ, Luthra A, Sligar SG, et al. Resonance Raman spectroscopy of the oxygenated intermediates of human CYP19A1 implicates a compound i intermediate in the final lyase step. J Am Chem Soc. 2014 Apr 2;136(13):4825–4828.
  • Hackett JC, Brueggemeier RW, Hadad CM. The final catalytic step of cytochrome P450 aromatase: A density functional theory study. J Am Chem Soc. 2005 Apr 13;127(14):5224–5237.
  • Sgrignani J, Iannuzzi M, Magistrato A. Role of water in the puzzling mechanism of the final aromatization step promoted by the human aromatase enzyme. Insights from QM/MM MD simulations. J Chem Inf Model. 2015 Oct;55(10):2218–2226.
  • Spinello A, Pavlin M, Casalino L, et al. A dehydrogenase dual hydrogen abstraction mechanism promotes estrogen biosynthesis: can we expand the functional annotation of the aromatase enzyme? Chem Eur J. 2018 Jul 25;24(42):10840–10849.
  • Nilsson S, Makela S, Treuter E, et al. Mechanisms of estrogen action. Physiol Rev. 2001 Oct;81(4):1535–1565.
  • Su B, Wong C, Hong Y, et al. Growth factor signaling enhances aromatase activity of breast cancer cells via post-transcriptional mechanisms. J Steroid Biochem Mol Biol. 2011 Feb;123(3–5):101–108.
  • Catalano S, Barone I, Giordano C, et al. Rapid estradiol/ERalpha signaling enhances aromatase enzymatic activity in breast cancer cells. Mol Endocrinol. 2009 Oct;23(10):1634–1645.
  • Barone I, Giordano C, Malivindi R, et al. Estrogens and PTP1B function in a novel pathway to regulate aromatase enzymatic activity in breast cancer cells. Endocrinology. 2012 Nov;153(11):5157–5166.
  • Ghosh D, Lo J, Egbuta C. Recent progress in the discovery of next generation inhibitors of aromatase from the structure-function perspective. J Med Chem. 2016 Jun 9; 59(11):5131–5148.
  • Lewis JS, Jordan VC. Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutat Res. 2005 Dec 11;591(1–2):247–263.
  • McDonnell DP, Wardell SE, Norris JD. Oral Selective Estrogen Receptor Downregulators (SERDs), a breakthrough endocrine therapy for breast cancer. J Med Chem. 2015 Jun 25;58(12):4883–4887.
  • Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of Tamoxifen and Raloxifene (STAR) P-2 trial. Jama. 2006 Jun 21;295(23):2727–2741.
  • Group EBCTC. Polychemotherapy for early breast cancer: an overview of the randomised trials. Early breast cancer trialists’ collaborative group. Lancet. 1998 Sep 19;352(9132):930–942.
  • Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst. 1998 Sep 16;90(18):1371–1388.
  • Masri S, Lui K, Phung S, et al. Characterization of the weak estrogen receptor alpha agonistic activity of exemestane. Breast Cancer Res Treat. 2009 Aug;116(3):461–470.
  • Amaral C, Borges M, Melo S, et al. Apoptosis and autophagy in breast cancer cells following exemestane treatment. PLoS One. 2012;7(8):e42398.
  • Bonneterre J, Buzdar A, Nabholtz JM, et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer. 2001 Nov 1;92(9):2247–2258.
  • Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO international consensus guidelines for Advanced Breast Cancer (ABC 4)dagger. Ann Oncol. 2018 Aug 1;29(8):1634–1657.
  • Khosrow-Khavar F, Filion KB, Al-Qurashi S, et al. Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials. Ann Oncol. 2017 Mar 1;28(3):487–496.
  • Amir E, Seruga B, Niraula S, et al. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst. 2011 Sep 7;103(17):1299–1309.
  • Aapro MS. Long-term implications of bone loss in breast cancer. Breast. 2004 Dec;13(Suppl 1):S29–37.
  • Augusto TV, Correia-da-Silva G, Rodrigues CMP, et al. Acquired resistance to aromatase inhibitors: where we stand! Endocr Relat Cancer. 2018 May;25(5):R283–R301.
  • Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013 Dec;45(12):1446–1451.
  • Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013 Dec;45(12):1439–1445.
  • Pavlin M, Spinello A, Pennati M, et al. A Computational Assay of estrogen receptor alpha antagonists reveals the key common structural traits of drugs effectively fighting refractory breast cancers. Sci Rep. 2018 Jan 12;8(1):649.
  • Fanning SW, Greene GL. Next-generation ERalpha inhibitors for endocrine-resistant ER+ breast cancer. Endocrinology. 2019 Apr 1;160:(4)759–769.
  • Scott JS, Bailey A, Buttar D, et al. Tricyclic indazoles-a novel class of selective estrogen receptor degrader antagonists. J Med Chem. 2019 Feb 14;62(3):1593–1608.
  • SW F, Hodges-Gallagher L, DC M, et al. Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity. Nat Commun. 2018 Jun 18;9(1):2368.
  • Kahraman M, Govek SP, Nagasawa JY, et al. Maximizing ER-alpha degradation maximizes activity in a tamoxifen-resistant breast cancer model: identification of GDC-0927. ACS Med Chem Lett. 2019 Jan 10;10(1):50–55.
  • Hanamura T, Hayashi SI. Overcoming aromatase inhibitor resistance in breast cancer: possible mechanisms and clinical applications. Breast Cancer. 2018 Jul;25(4):379–391.
  • Amaral C, Varela C, Azevedo M, et al. Effects of steroidal aromatase inhibitors on sensitive and resistant breast cancer cells: aromatase inhibition and autophagy. J Steroid Biochem Mol Biol. 2013;135:51–59.
  • Furman C, Hao MH, Prajapati S, et al. Estrogen receptor covalent antagonists: the best is yet to come. Cancer Res. 2019 Apr 15;79(8):1740–1745.
  • Patel HK, Bihani T. Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs) in cancer treatment. Pharmacol Ther. 2018 Jun;186:1–24.
  • De Vivo M, Masetti M, Bottegoni G, et al. Role of molecular dynamics and related methods in drug discovery. J Med Chem. 2016 May 12;59(9):4035–4061.
  • Sgrignani J, Cavalli A, Colombo G, et al. Enzymatic and inhibition mechanism of human aromatase (CYP19A1) enzyme. A computational perspective from QM/MM and classical molecular dynamics simulations. Mini Rev Med Chem. 2016;16(14):1112–1124.
  • Favia AD, Nicolotti O, Stefanachi A, et al. Computational methods for the design of potent aromatase inhibitors. Expert Opin Drug Discov. 2013 Apr;8(4):395–409.
  • Spinello A, Magistrato A. An omics perspective to the molecular mechanisms of anticancer metallo-drugs in the computational microscope era. Expert Opin Drug Discov. 2017 Aug;12(8):813–825.
  • Sgrignani J, Magistrato A. First-principles modeling of biological systems and structure-based drug-design. Curr Comput Aided Drug Des. 2013 Mar;9(1):15–34.
  • Lipton A, Santen RJ. Medical adrenalectomy using aminoglutethimide and dexamethasone in advanced breast cancer. Cancer. 1974 Feb;33(2):503–512.
  • Dexter RN, Fishman LM, Ney RL, et al. Inhibition of adrenal corticosteroid synthesis by aminoglutethimide: studies of the mechanism of action. J Clin Endocrinol Metab. 1967 Apr;27(4):473–480.
  • Graves PE, Salhanick HA. Stereoselective inhibition of aromatase by enantiomers of aminoglutethimide. Endocrinology. 1979 Jul;105(1):52–57.
  • Di Salle E, Ornati G, Giudici D, et al. Exemestane (FCE 24304), a new steroidal aromatase inhibitor. J Steroid Biochem Mol Biol. 1992 Sep;43(1–3):137–143.
  • Coombes RC, Goss P, Dowsett M, et al. 4-Hydroxyandrostenedione in treatment of postmenopausal patients with advanced breast cancer. Lancet. 1984 Dec 1;2(8414):1237–1239.
  • Dowsett M, Cunningham DC, Stein RC, et al. Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients. Cancer Res. 1989 Mar 1;49(5):1306–1312.
  • Stein RC, Dowsett M, Hedley A, et al. The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer. Br J Cancer. 1990 Oct;62(4):679–683.
  • Santen RJ, Langecker P, Santner SJ, et al. Potency and specificity of CGS-16949A as an aromatase inhibitor. Endocr Res. 1990;16(1):77–91.
  • Browne LJ, Gude C, Rodriguez H, et al. Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease. J Med Chem. 1991 Feb;34(2):725–736.
  • Lonning PE, Jacobs S, Jones A, et al. The influence of CGS 16949A on peripheral aromatisation in breast cancer patients. Br J Cancer. 1991 May;63(5):789–793.
  • Tominaga T, Adachi I, Sasaki Y, et al. Double-blind randomised trial comparing the non-steroidal aromatase inhibitors letrozole and fadrozole in postmenopausal women with advanced breast cancer. Ann Oncol. 2003 Jan;14(1):62–70.
  • Brodie AM, Njar VC. Aromatase inhibitors in advanced breast cancer: mechanism of action and clinical implications. J Steroid Biochem Mol Biol. 1998 Jul;66(1–2):1–10.
  • Ghosh D, Lo J, Morton D, et al. Novel aromatase inhibitors by structure-guided design. J Med Chem. 2012 Oct 11;55(19):8464–8476.
  • Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. New Engl J Med. 2003 Jun 12;348(24):2431–2442.
  • Miller WR. Biology of aromatase inhibitors: pharmacology/endocrinology within the breast. Endocr Relat Cancer. 1999 Jun;6(2):187–195.
  • Thiantanawat A, Long BJ, Brodie AM. Signaling pathways of apoptosis activated by aromatase inhibitors and antiestrogens. Cancer Res. 2003 Nov 15;63(22):8037–8050.
  • Itoh T, Karlsberg K, Kijima I, et al. Letrozole-, anastrozole-, and tamoxifen-responsive genes in MCF-7aro cells: a microarray approach. Mol Cancer Res. 2005 Apr;3(4):203–218.
  • Sobral AF, Amaral C, Correia-da-Silva G, et al. Unravelling exemestane: from biology to clinical prospects. J Steroid Biochem Mol Biol. 2016;163:1–11.
  • Chan HJ, Petrossian K, Chen S. Structural and functional characterization of aromatase, estrogen receptor, and their genes in endocrine-responsive and -resistant breast cancer cells. J Steroid Biochem Mol Biol. 2016 Jul;161:73–83.
  • Buzdar AU, Jonat W, Howell A, et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex study group. Cancer. 1998 Sep 15;83(6):1142–1152.
  • Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Aug 1;386(9992):433–443.
  • Schuster D, Laggner C, Steindl TM, et al. Pharmacophore modeling and in silico screening for new P450 19 (aromatase) inhibitors. J Chem Inf Model. 2006 May-Jun;46(3):1301–1311.
  • Neves MA, Dinis TC, Colombo G, et al. Fast three dimensional pharmacophore virtual screening of new potent non-steroid aromatase inhibitors. J Med Chem. 2009 Jan 8;52(1):143–150.
  • Neves MA, Dinis TC, Colombo G, et al. An efficient steroid pharmacophore-based strategy to identify new aromatase inhibitors. Eur J Med Chem. 2009 Oct;44(10):4121–4127.
  • Cramer RD, Patterson DE, Bunce JD. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc. 1988 Aug 1;110(18):5959–5967.
  • Recanatini M. Comparative molecular field analysis of non-steroidal aromatase inhibitors related to fadrozole. J Comput Aided Mol Des. 1996 Feb;10(1):74–82.
  • Recanatini M, Cavalli A. Comparative molecular field analysis of non-steroidal aromatase inhibitors: an extended model for two different structural classes. Bioorg Med Chem. 1998 Apr;6(4):377–388.
  • Recanatini M, Bisi A, Cavalli A, et al. A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase. J Med Chem. 2001 Mar 1;44(5):672–680.
  • Gobbi S, Cavalli A, Rampa A, et al. Lead optimization providing a series of flavone derivatives as potent nonsteroidal inhibitors of the cytochrome P450 aromatase enzyme. J Med Chem. 2006 Jul 27;49(15):4777–4780.
  • Dassault Systèmes BIOVIA. Discovery studio modeling environment, release. Vol. 2017. San Diego: Dassault Systèmes; 2016.
  • Su B, Tian R, Darby MV, et al. Novel sulfonanilide analogs decrease aromatase activity in breast cancer cells: synthesis, biological evaluation, and ligand-based pharmacophore identification. J Med Chem. 2008 Mar 13;51(5):1126–1135.
  • Ghosh D, Griswold J, Erman M, et al. Structural basis for androgen specificity and oestrogen synthesis in human aromatase. Nature. 2009 Jan 8;457(7226):219–223.
  • Williams PA, Cosme J, Ward A, et al. Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature. 2003 Jul 24;424(6947):464–468.
  • Williams PA, Cosme J, Vinkovic DM, et al. Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science. 2004 Jul 30;305(5684):683–686.
  • Favia AD, Cavalli A, Masetti M, et al. Three-dimensional model of the human aromatase enzyme and density functional parameterization of the iron-containing protoporphyrin IX for a molecular dynamics study of heme-cysteinato cytochromes. Proteins. 2006 Mar 1;62(4):1074–1087.
  • Karkola S, Holtje HD, Wahala K. A three-dimensional model of CYP19 aromatase for structure-based drug design. J Steroid Biochem Mol Biol. 2007 Jun-Jul;105(1–5):63–70.
  • Graham-Lorence S, Amarneh B, White RE, et al. A three-dimensional model of aromatase cytochrome P450. Protein Sci. 1995 Jun;4(6):1065–1080.
  • Numazawa M, Kamiyama T, Tachibana M, et al. Synthesis and structure-activity relationships of 6-substituted androst-4-ene analogs as aromatase inhibitors. J Med Chem. 1996 May 24;39(11):2245–2252.
  • Cavalli A, Greco G, Novellino E, et al. Linking CoMFA and protein homology models of enzyme-inhibitor interactions: an application to non-steroidal aromatase inhibitors. Bioorg Med Chem. 2000 Dec;8(12):2771–2780.
  • Kao YC, Korzekwa KR, Laughton CA, et al. Evaluation of the mechanism of aromatase cytochrome P450. A site-directed mutagenesis study. Eur J Biochem. 2001 Jan;268(2):243–251.
  • Hong Y, Rashid R, Chen S. Binding features of steroidal and nonsteroidal inhibitors. Steroids. 2011 Jul;76(8):802–806.
  • Magistrato A, Sgrignani J, Krause R, et al. Single or multiple access channels to the CYP450s active site? An answer from free energy simulations of the human aromatase enzyme. J Phys Chem Lett. 2017 May 4;8(9):2036–2042.
  • Maurelli S, Chiesa M, Giamello E, et al. Direct spectroscopic evidence for binding of anastrozole to the iron heme of human aromatase. Peering into the mechanism of aromatase inhibition. Chem Commun. 2011 Oct 14;47(38):10737–10739.
  • Galeazzi R, Massaccesi L. Insight into the binding interactions of CYP450 aromatase inhibitors with their target enzyme: a combined molecular docking and molecular dynamics study. J Mol Model. 2012 Mar;18(3):1153–1166.
  • Sgrignani J, Casalino L, Doro F, et al. Can multiscale simulations unravel the function of metallo-enzymes to improve knowledge-based drug discovery? Future Med Chem. 2019 Apr;11(7):771–791.
  • Vidossich P, Magistrato A. QM/MM molecular dynamics studies of metal binding proteins. Biomolecules. 2014 Jul 8;4(3):616–645.
  • Spinello A, Barone G, Cappello F, et al. The binding mechanism of epolactaene to Hsp60 unveiled by in silico modelling. Chemistryselect. 2016 Apr;1(4):759–765.
  • Casalino L, Palermo G, Rothlisberger U, et al. Who activates the nucleophile in ribozyme catalysis? An answer from the splicing mechanism of group ii introns. J Am Chem Soc. 2016 Aug 24;138(33):10374–10377.
  • Sgrignani J, Magistrato A. QM/MM MD simulations on the enzymatic pathway of the human flap endonuclease (hFEN1) elucidating common cleavage pathways to RNase H enzymes. ACS Catal. 2015 Jun;5(6):3864–3875.
  • Ghosh D, Egbuta C, Lo J. Testosterone complex and non-steroidal ligands of human aromatase. J Steroid Biochem Mol Biol. 2018 Jul;181:11–19.
  • Roleira FMF, Varela C, Amaral C, et al. C-6alpha- vs C-7alpha-substituted steroidal aromatase inhibitors: which is better? Synthesis, biochemical evaluation, docking studies, and structure-activity relationships. J Med Chem. 2019 Apr 11;62(7):3636–3657.
  • Caporuscio F, Rastelli G, Imbriano C, et al. Structure-based design of potent aromatase inhibitors by high-throughput docking. J Med Chem. 2011 Jun 23;54(12):4006–4017.
  • Ferlin MG, Carta D, Bortolozzi R, et al. Design, synthesis, and structure-activity relationships of azolylmethylpyrroloquinolines as nonsteroidal aromatase inhibitors. J Med Chem. 2013 Oct 10;56(19):7536–7551.
  • Pingaew R, Prachayasittikul V, Mandi P, et al. Synthesis and molecular docking of 1,2,3-triazole-based sulfonamides as aromatase inhibitors. Bioorg Med Chem. 2015 Jul 1;23(13):3472–3480.
  • Pingaew R, Mandi P, Prachayasittikul V, et al. Synthesis, molecular docking, and QSAR study of sulfonamide-based indoles as aromatase inhibitors. Eur J Med Chem. 2018 Jan 1;143:1604–1615.
  • Kang H, Xiao X, Huang C, et al. Potent aromatase inhibitors and molecular mechanism of inhibitory action. Eur J Med Chem. 2018 Jan 1;143:426–437.
  • Varela C, Tavares Da Silva EJ, Amaral C, et al. New structure-activity relationships of A- and D-ring modified steroidal aromatase inhibitors: design, synthesis, and biochemical evaluation. J Med Chem. 2012 Apr 26;55(8):3992–4002.
  • Varela CL, Amaral C, Correia-da-Silva G, et al. Exploring new chemical functionalities to improve aromatase inhibition of steroids. Bioorg Med Chem. 2016 Jun 15;24(12):2823–2831.
  • Polic V, Auclair K. Allosteric activation of cytochrome P450 3A4 via progesterone bioconjugation. Bioconjug Chem. 2017 Apr 19;28(4):885–889.
  • Denisov IG, Baylon JL, Grinkova YV, et al. Drug-drug interactions between atorvastatin and dronedarone mediated by monomeric CYP3A4. Biochemistry. 2018 Feb 6;57(5):805–816.
  • Lu WJ, Desta Z, Flockhart DA. Tamoxifen metabolites as active inhibitors of aromatase in the treatment of breast cancer. Breast Cancer Res Treat. 2012 Jan;131(2):473–481.
  • Egbuta C, Lo J, Ghosh D. Mechanism of inhibition of estrogen biosynthesis by azole fungicides. Endocrinology. 2014 Dec;155(12):4622–4628.
  • Rampogu S, Son M, Park C, et al. Sulfonanilide derivatives in identifying novel aromatase inhibitors by applying docking, virtual screening, and MD simulations studies. Biomed Res Int. 2017;2017:2105610.
  • Halgren TA. Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model. 2009 Feb;49(2):377–389.
  • Sgrignani J, Bon M, Colombo G, et al. Computational approaches elucidate the allosteric mechanism of human aromatase inhibition: a novel possible route to Small-molecule regulation of CYP450s activities?. J Chem Inf Model. 2014 Oct 27;54(10):2856–2868.
  • Sgrignani J, Magistrato A. Influence of the membrane lipophilic environment on the structure and on the substrate access/egress routes of the human aromatase enzyme. A computational study. J Chem Inf Model. 2012 Jun 25;52(6):1595–1606.
  • Spinello A, Martini S, Berti F, et al. Rational design of allosteric modulators of the aromatase enzyme: an unprecedented therapeutic strategy to fight breast cancer. Eur J Med Chem. 2019 Apr;15(168):253–262.
  • Ritacco I, Spinello A, Ippoliti E, et al. The post-translational regulation of CYP450s metabolism as revealed by all-atoms simulations of the aromatase enzyme. J Chem Inf Model. 2019 Jun 24;59(6):2930–2940.
  • Jelovac D, Macedo L, Goloubeva OG, et al. Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model. Cancer Res. 2005 Jun 15;65(12):5439–5444.
  • Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002 Jun 22;359(9324):2131–2139.
  • Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. New Engl J Med. 2012 Aug 2;367(5):435–444.
  • Mehta RS, Barlow WE, Albain KS, et al. Overall survival with fulvestrant plus anastrozole in metastatic breast cancer. New Engl J Med. 2019 Mar 28;380(13):1226–1234.
  • Lu WJ, Xu C, Pei Z, et al. The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents. Breast Cancer Res Treat. 2012 May;133(1):99–109.
  • Lv W, Liu J, Lu D, et al. Synthesis of mixed (E,Z)-, (E)-, and (Z)-norendoxifen with dual aromatase inhibitory and estrogen receptor modulatory activities. J Med Chem. 2013 Jun 13;56(11):4611–4618.
  • Lv W, Liu J, Skaar TC, et al. Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities. J Med Chem. 2015 Mar 26;58(6):2623–2648.
  • Lv W, Liu J, Skaar TC, et al. Synthesis of triphenylethylene bisphenols as aromatase inhibitors that also modulate estrogen receptors. J Med Chem. 2016 Jan 14;59(1):157–170.
  • Zhao LM, Jin HS, Liu J, et al. A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors alpha and beta. Bioorg Med Chem. 2016 Nov 1;24(21):5400–5409.
  • Amaral C, Varela CL, Mauricio J, et al. Anti-tumor efficacy of new 7alpha-substituted androstanes as aromatase inhibitors in hormone-sensitive and resistant breast cancer cells. J Steroid Biochem Mol Biol. 2017;171:218–228.
  • Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO international consensus guidelines for Advanced Breast Cancer (ABC 3). Breast. 2017;31:244–259.
  • Ferraro M, D’Annessa I, Moroni E, et al. Allosteric modulators of HSP90 and HSP70: dynamics meets function through structure-based drug design. J Med Chem. 2019 Jan 10;62(1):60–87.
  • Legnani L, Compostella F, Sansone F, et al. Cone Calix[4]arenes with orientable glycosylthioureido groups at the upper rim: an in-depth analysis of their symmetry properties. J Org Chem. 2015 Aug 7;80(15):7412–7418.
  • Pruthi S, Heisey RE, Bevers TB. Chemoprevention for Breast Cancer. Ann Surg Oncol. 2015 Oct;22(10):3230–3235.
  • Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. New Engl J Med. 2011 Jun 23;364(25):2381–2391.
  • Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014 Mar 22;383(9922):1041–1048.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.