Flexible small molecular anti-estrogens with N,N-dialkylated-2,5-diethoxy-4-morpholinoaniline scaffold targets multiple estrogen receptor conformations

References

• Bjornstrom L, Sjoberg M. Mechanisms of estrogen receptor signaling: Convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 2005; 19:833-42; PMID:15695368; https://doi.org/10.1210/me.2004-0486
   PubMed Web of Science ®Google Scholar
• Levin ER. Integration of the extranuclear and nuclear Actions of Estrogen. Mol Endocrinol 2005; 19:1951-9; PMID:15705661; https://doi.org/10.1210/me.2004-0390
   PubMed Web of Science ®Google Scholar
• Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F, Giguère V. Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor β. Mol Endocrinol 1997; 11:353-65; PMID:9058381; https://doi.org/10.1210/mend.11.3.9902
   PubMed Web of Science ®Google Scholar
• Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjöld M, Gustafsson JA. Human Estrogen Receptor β-Gene Structure, Chromosomal Localization, and Expression Pattern. J Clin Endocrinol Metab 1997; 82:4258-65; PMID:9398750; https://doi.org/10.1210/jcem.82.12.4470
   PubMed Web of Science ®Google Scholar
• Ponglikitmongkol M, Green S, Chambon P. Genomic organization of the human oestrogen receptor gene. EMBO J 1988; 7:3385-8; PMID:3145193
   PubMed Web of Science ®Google Scholar
• Bruning JB, Parent AA, Gil G, Zhao M, Nowak J, Pace MC, Smith CL, Afonine PV, Adams PD, Katzenellenbogen JA, et al. Coupling of receptor conformation and ligand orientation determine graded activity. Nat Chem Biol 2010; 6:837-43; PMID:20924370; https://doi.org/10.1038/nchembio.451
   PubMed Web of Science ®Google Scholar
• Beato M, Sanchez-Pacheco A. Interaction of steroid hormone receptors with the transcription initiation complex. Endocr Rev 1996; 17:587-609; PMID:8969970; https://doi.org/10.1210/edrv-17-6-587
   PubMed Web of Science ®Google Scholar
• Cavailles V, Dauvois S, Danielian PS, Parker MG. Interaction of protein with transcriptionally active estrogen receptors. Proc Natl Acad Sci U S A 1994; 91:10009-13; PMID:7937828; https://doi.org/10.1073/pnas.91.21.10009
   PubMed Web of Science ®Google Scholar
• L'Horset F, Dauvois S, Heery DM, Cavailles V, Parker MG. RIP-140 interacts with multiple nuclear receptors by means of two distinct sites. Mol Cell Biol 1996; 16:6029-36; PMID:8887632; https://doi.org/10.1128/MCB.16.11.6029
   PubMed Web of Science ®Google Scholar
• vom Baur E, Zechel C, Heery DM, Heine MJ, Garnier JM, Vivat V, Le Douarin B, Gronemeyer H, Chambon P, Losson R. Differential ligand-dependent interactions between AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1. EMBO J 1996; 15:110-24; PMID:8598193
   PubMed Web of Science ®Google Scholar
• Saville B, Wormke M, Wang F, Nguyen T, Enmark E, Kuiper G, Gustafsson JA, Safe S. Ligand-,cell-,and estrogen receptor subtype (alpha/beta)-dependent activation of GC-rich (Sp1) promoter elements. J Biol Chem 2000; 275:5379-87; PMID:10681512; https://doi.org/10.1074/jbc.275.8.5379
   PubMed Web of Science ®Google Scholar
• Peters GA, Khan SA. Estrogen receptor domains E and F role in dimerization and interaction with coactivator RIP-140. Mol Endocrinol 1999; 13:286-96; PMID:9973258; https://doi.org/10.1210/mend.13.2.0244
   PubMed Web of Science ®Google Scholar
• Hall JM, McDonnell DP, Korach KS. Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements. Mol Endocrinol 2002; 16:469-86; PMID:11875105; https://doi.org/10.1210/mend.16.3.0814
   PubMed Web of Science ®Google Scholar
• O'Lone R, Frith MC, Karlsson EK, Hansen U. Genomic targets of nuclear estrogen receptors. Mol Endocrinol 2004; 18:1859-4875; PMID:15031323; https://doi.org/10.1210/me.2003-0044
   PubMed Web of Science ®Google Scholar
• Wronski TJ, Clintron M, Doherty SL, Dann LM. Estrogen treatment prevents osteopenia and depresses bone turnover in ovariectomized rats. Endocrinology 1988; 123:681-6; PMID:3396505; https://doi.org/10.1210/endo-123-2-681
   PubMed Web of Science ®Google Scholar
• Riggins R, Schrecengost R, Guerrero M, Bouton A. Pathways to tamoxifen resistance. Cancer Lett 2007; 256:1-24; PMID:17475399; https://doi.org/10.1016/j.canlet.2007.03.016
   PubMed Web of Science ®Google Scholar
• Lerner LJ, Holthaus JF, Thompson CR. A non-steroidal estrogen antagonist 1-(p-2-diethylaminoethoxyphenyl)-1-phenyl-2-p-methoxyphenylethanol. Endocrinology 1958; 63:295-318; PMID:13574085; https://doi.org/10.1210/endo-63-3-295
   PubMed Web of Science ®Google Scholar
• Howell S, Johnston SRD, Howell A. The use of selective estrogen receptor modulators and selective estrogen receptor down-regulators in breast cancer. Best Pract Res Clin Endocrinol Metab 2004; 18:47-66; PMID:14687597; https://doi.org/10.1016/j.beem.2003.08.002
   PubMed Web of Science ®Google Scholar
• Jordan VC. Tamoxifen: A most unlikely pioneering medicine. Nat Rev Drug Discovery 2003; 2:205-13; PMID:12612646; https://doi.org/10.1038/nrd1031
   PubMed Web of Science ®Google Scholar
• Ring A, Dowsett M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer 2004; 11:643-58; PMID:15613444; https://doi.org/10.1677/erc.1.00776
   PubMed Web of Science ®Google Scholar
• Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros Alencar VH, Badran A, Bonfill X, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013; 381:805-15; PMID:23219286; https://doi.org/10.1016/S0140-6736(12)61963-1
   PubMed Web of Science ®Google Scholar
• Kangas L, Nieminen AL, Blanco G. A new triphenylethylene compound, Fc-1157a. II. Antitumor effects. Cancer Chemother Pharmacol 1986; 17:109-13; PMID:2941177; https://doi.org/10.1007/BF00306737
   PubMed Web of Science ®Google Scholar
• Chander SK, McCague R, Luqmani Y, Newton C, Dowsett M, Jarman M, Coombes RC. Pyrrolidino-4-iodatamifen and 4-iodotamoxifen, new analogues of the antiestrogen tamoxifen for the treatment of breast cancer. Cancer Res 1991; 51:5851-8; PMID:1933854
   PubMed Web of Science ®Google Scholar
• Loser R, Seibel K, Eppenberger U. No loss of estrogen or anti-estrogenic activity after demethylation of droloxifene (3-OH-tamoxifen). Int J Cancer 1985; 36:701-3; PMID:4066073; https://doi.org/10.1002/ijc.2910360614
   PubMed Web of Science ®Google Scholar
• Toko T, Sugimoto Y, Matsuo K. TAT-59, a new triphenylethylene derivative with antitumor activity against hormone-dependent tumours. Eur J Cancer Clin Oncol 1990; 26:397-404; PMID:2141500; https://doi.org/10.1016/0277-5379(90)90241-K
   PubMedGoogle Scholar
• Toko T, Shibata J, Nukatsuka M. Antiestrogenic activity of DP-TAT-59, an active metabolite of TAT-59 against human breast cancer. Cancer Chemother Pharmacol 1997; 39:390-8; PMID:9054952; https://doi.org/10.1007/s002800050589
   PubMed Web of Science ®Google Scholar
• Palkowitz AD, Glasebrook AL, Thrasher KJ. Discovery and synthesis of [6-hydroxy-3-[4-[2-(1-piperidinly)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]b enzo[b]thiophene: A novel, highly potent, selective estrogen receptor modulator. J Med Chem 1997; 40:1407-16; PMID:9154963; https://doi.org/10.1021/jm970167b
   PubMed Web of Science ®Google Scholar
• Clemens JA, Bennett DR, Black LJ. Effects of a new antiestrogen, keoxifene (LY 156758), on growth of carcinogen-induced mammary tumours and on LH and prolactin levels. Life Sci 1983; 32:2869-75; PMID:6406781; https://doi.org/10.1016/0024-3205(83)90323-5
   PubMed Web of Science ®Google Scholar
• Gauthier S, Caron B, Cloutier J. (S)-(+)-4-[7-(2,2-dimethyl-1-oxopropoxy)-4-methyl-2[4-[2-(1-piperidinyl)-ethoxy]phenyl]-SH-1-benzopyran-3-yl]-phenyl 2, 2-dimethylpropanoate 9EM-800): A highly potent, specific, and orally active nonsteroidal antiestrogen. J Med Chem 1997; 40:2117-22; PMID:9216828; https://doi.org/10.1021/jm970095o
   PubMed Web of Science ®Google Scholar
• Jones CD, Suarez T, Massey EH, Black LJ, Tinsley FC. Synthesis and antiestrogenic activity of [3,4-dihydro-2-(4-methoxyphenyl)-1-naphthalenyl]methanone, methanesulfonic acid salt. J Med Chem 1979; 22:962-6; PMID:490541; https://doi.org/10.1021/jm00194a015
   PubMed Web of Science ®Google Scholar
• Coopman P, Garcia M, Brunner N. Anti-proliferative and anti-estrogenic effects of ICI 164,384 and ICI 182,780 in 4-OH-tamoxifene-resistant human breast cancer cells. Int J Cancer 1994; 56:295-300; PMID:8314314; https://doi.org/10.1002/ijc.2910560225
   PubMed Web of Science ®Google Scholar
• Brunner N, Frandsen TL, Holst-Hansen C. MCF7/LCC2: A 4-hydroxytamoxifen resistant human breast cancer variant that retains sensitivity to the steroidal antiestrogen ICI 182,780. Cancer Res 1993; 53:3229-32; PMID:8324732
   PubMed Web of Science ®Google Scholar
• Hu XF, Veroni M, De Luise M. Circumvention of tamoxifen resistance by the pure anti-estrogen ICI 182,780. Int J Cancer 1993; 55:873-6; PMID:8244585; https://doi.org/10.1002/ijc.2910550529
   PubMed Web of Science ®Google Scholar
• Brunner N, Boysen B, Jirus S. MCF7/LCC9: An antiestrogen-resistant MCF-7 variant in which acquired resistance to the steroidal antiestrogen ICI182,780 confers an early cross-resistance to the nonsteroidal antiestrogen tamoxifen. Cancer Res 1997; 57:3486-93; PMID:9270017
   PubMed Web of Science ®Google Scholar
• Osborne CK, Coronado-Heinsohn EB, Hilsenbeck SG. Comparison of the effects of a pure antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 1995; 87:746-50; PMID:7563152; https://doi.org/10.1093/jnci/87.10.746
   PubMed Web of Science ®Google Scholar
• Wakeling AE, Dukes M, Bowler JA. A potent specific pure antiestrogen with clinical potential. Cancer Res 1991; 51:3867-73; PMID:1855205
   PubMed Web of Science ®Google Scholar
• Parker MG. Action of ‘pure’ antiestrogens in inhibiting estrogen receptor action. Breast Cancer Res Treat 1993; 26:131-7; PMID:8219250; https://doi.org/10.1007/BF00689686
   PubMed Web of Science ®Google Scholar
• Kuiper G, Gustafsson J-Å. The novel estrogen receptor-beta subtype: Potential role in the cell- and promoter-specific actions of estrogens and anti-estrogens. FEBS Lett 1997; 410:87-90; PMID:9247129; https://doi.org/10.1016/S0014-5793(97)00413-4
   PubMed Web of Science ®Google Scholar
• Katzenellenbogen BS, Korach KS. A new actor in the estrogen receptor drama- enter ER-beta. Endocrinology 1997; 138:861-2; PMID:9048583; https://doi.org/10.1210/endo.138.3.5080
   PubMed Web of Science ®Google Scholar
• Mosselman S, Polman J, Dijkema R. ER beta: Identification and characterization of a novel human estrogen receptor. FEBS Lett 1996; 392:49-53; PMID:8769313; https://doi.org/10.1016/0014-5793(96)00782-X
   PubMed Web of Science ®Google Scholar
• Webb P, Nguyen P, Kushner PJ. Differential SERM effects on corepressor binding dictate ER alpha activity in vivo. J Biol Chem 2003; 278:6912-20; PMID:12482846; https://doi.org/10.1074/jbc.M208501200
   PubMed Web of Science ®Google Scholar
• Wijayaratne AL, McDonnell DP. The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonist, and selective estrogen receptor modulators. J Biol Chem 2001; 276:35684-92; PMID:11473106; https://doi.org/10.1074/jbc.M101097200
   PubMed Web of Science ®Google Scholar
• Hoffman J, Bohlmann R, Heinrich N. Second generation of estrogen receptor destabilising compounds-pharmacological profile in antiestrogen-sensitive or -resistant breast cancer. Breast Cancer Res Treat 2002; 76:27; PMID:12408373
   PubMed Web of Science ®Google Scholar
• Kieser KJ, Kim DW, Carlson KE, Katzenellenbogen BS, Katzenellenbogen JA. Characterization of the pharmacophore properties of novel selective estrogen receptor downregulators (SERDs). J Med Chem 2010; 53:3320-9; PMID:20334372; https://doi.org/10.1021/jm100047k
   PubMed Web of Science ®Google Scholar
• McDonnell DP, Clemm DL, Hermann T, Goldmann ME, Pike JW. Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol 1995; 9:659-69; PMID:8592512; https://doi.org/10.1210/mend.9.6.8592512
   PubMed Web of Science ®Google Scholar
• Wijayaratne AL, Nagel SC, Paige LA, Christensen DJ, Norris JD, Fowlkes DM, McDonnell DP. Comparative analyses of mechanistic differences among antiestrogens. Endocrinology 1999; 140:5828-40; PMID:10579349; https://doi.org/10.1210/endo.140.12.7164
   PubMed Web of Science ®Google Scholar
• MacGregor-Shafer JI, Liu H, Bentrem D, Zapf J, Jordan VC. Allosteric silencing of activating function 1 in the 4-hydroxytamoxifen estrogen receptor complex by substituting glycine for aspartate at amino acid 351. Cancer Res 2000; 60:5097-105; PMID:11016635
   PubMed Web of Science ®Google Scholar
• Norris JD, Paige LA, Christensen DJ, Chang CY, Huacani MR, Fan D, Hamilton PT, Fowlkes DM, McDonnell DP. Peptide antagonists of the human estrogen receptor. Science 1999; 285:744-6; PMID:10426998; https://doi.org/10.1126/science.285.5428.744
   PubMed Web of Science ®Google Scholar
• Paige LA, Christensen DJ, Gronemeyer H, Norris JD, Gottlin EB, Padilola KM, Chang CY, Ballas LM, Hamilton PT, McDonnell DP, et al. Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER Beta. Proc Natl Acad Sci U S A 1999; 96:3999-4004; PMID:10097152; https://doi.org/10.1073/pnas.96.7.3999
   PubMed Web of Science ®Google Scholar
• Levenson AS, MacGregor-Shafer JI, Bentrem D, Pease KM, Jordan VC. Control of the estrogen-like actions of tamoxifen-estrogen receptor complex by the surface amino acid at position 251. J Steroid Biochem Mol Biol 2001; 76:61-70; PMID:11384864; https://doi.org/10.1016/S0960-0760(00)00143-6
   PubMed Web of Science ®Google Scholar
• Wolf DM, Jordan VC. Characterization of tamoxifen stimulated MCF-7 tumor variants growth in athymic mice. Breast Cancer Res Treat 1994; 31:117-27; PMID:7981452; https://doi.org/10.1007/BF00689682
   PubMed Web of Science ®Google Scholar
• Wolf DM, Jordan VC. The estrogen receptor from a tamoxifen stimulated MCF-7 tumor variant contains a point mutation in the ligand binding domain. Breast Cancer Res Treat 1994; 31:129-38; PMID:7981453; https://doi.org/10.1007/BF00689683
   PubMed Web of Science ®Google Scholar
• Levenson AS, Tonetti DA, Jordan VC. The oestrogen-like effect of 4-hydroxytamoxifen on induction of transforming growth factor alpha mRNA in MDA-MB-231 breast cancer cells stably expressing the oestrogen receptor. Br J Cancer 1998; 77:1812-9; PMID:9667651; https://doi.org/10.1038/bjc.1998.301
   PubMed Web of Science ®Google Scholar
• Wen J, Li R, Lu Y, Shupnik M. Decreased BRCA1 confers tamoxifen resistance in breast cancer cells by altering estrogen receptor-coregulator interactions. Oncogene 2009; 28:575-86; PMID:18997820; https://doi.org/10.1038/onc.2008.405
   PubMed Web of Science ®Google Scholar
• Backman TW, Cao Y, Girke T. ChemMine tools: An online service for analyzing and clustering small molecules. Nucleic Acids Res 2011; 39:W486-91; PMID:21576229; https://doi.org/10.1093/nar/gkr320
   PubMed Web of Science ®Google Scholar
• Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. The protein data bank. Nucleic Acids Res 2000; 28:235-42; PMID:10592235; https://doi.org/10.1093/nar/28.1.235
   PubMed Web of Science ®Google Scholar
• The UniProt Consortium. UniProt: The universal protein knowledgebase. Nucleic Acids Res 2017; 45:158-69; PMID:27899622; https://doi.org/10.1093/nar/gkw1099
   PubMed Web of Science ®Google Scholar
• Chakraborty S, Asare BK, Biswas PK, Rajnarayanan RV. Designer interface peptide grafts target estrogen receptor alpha dimerization. Biochem Biophys Res Commun 2016; 478:116-22; PMID:27462021; https://doi.org/10.1016/j.bbrc.2016.07.083
   PubMed Web of Science ®Google Scholar
• Srinivasan S, Nwachukwu JC, Parent AA, Cavett V, Nowak J, Hughes TS, Kojetin DJ, Katzenellenbogen JA, Nettles KW. Ligand-binding dynamics rewire cellular signaling via estrogen receptor-alpha. Nat Chem Biol 2013; 9:326-32; PMID:23524984; https://doi.org/10.1038/nchembio.1214
   PubMed Web of Science ®Google Scholar
• Cirillo F, Nassa G, Tarallo R, Stellato C, Filippo MRD, Ambrosino C, Baumann M, Nyman TA, Weisz A. Molecular mechanisms of selective estrogen receptor modulator activity in human breast cancer cells: Identification of novel nuclear cofactors of antiestrogen–ERα complexes by interaction proteomics. J Proteome Res 2013; 12:421-31; PMID:23170835; https://doi.org/10.1021/pr300753u
   PubMed Web of Science ®Google Scholar
• Powell E, Shanle E, Brinkman A, Li J, Keles S, Wisinski K, Huang W, Xu W. Identification of estrogen receptor dimer selective ligands reveals growth-inhibitory effects on cells that co-express ER alpha and ER beta. PLoS ONE 2012; 7:e30993; PMID:22347418; https://doi.org/10.1371/journal.pone.0030993
   PubMed Web of Science ®Google Scholar
• Powell E, Huang SX, Xu Y, Rajski SR, Wang Y, Peters N, Guo S, Xu HE, Hoffmann FM, Shen B, et al. Identification and characterization of a novel estrogenic ligand actinopolymorphol a. Biochem Pharmacol 2010; 80:1221-9; PMID:20599778; https://doi.org/10.1016/j.bcp.2010.06.030
   PubMed Web of Science ®Google Scholar