Design, Synthesis, and Preclinical Characterization of Novel, Highly Selective Indole Estrogens

Cp, Miller; Collini,; Bd, Tran; Ha, Harris; Yp, Kharode; Jt, Marzolf; Ra, Moran; Henderson, ra E; Rh, Bender; Rj, Unwalla; Lm, Greenberger; Jp, Yardley; Ma, Abou-Gharbia; Cr, Lyttle; Bs, Komm

doi:10.1021/jm010086m

Cited by 131 publications

(80 citation statements)

References 18 publications

(29 reference statements)

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“…and M.A.S. using a protocol described previously (Miller et al, 2001). All of the compounds were dissolved in 100% ethanol except for MG132, which was dissolved in dimethyl sulfoxide.…”

Section: Methodsmentioning

confidence: 99%

“…It was assembled by using RAL as a template and substituting an indole ring for the benzothiophene core (Miller et al, 2001;Komm et al, 2005). BZA binds to both ER␣ and ER␤, with a slightly higher affinity for ER␣; how-ever, it is less ER␣-selective than RAL, with an affinity for ER␣ that is approximately 10-fold lower than 17␤-estradiol (E2) (Miller et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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The Selective Estrogen Receptor Modulator Bazedoxifene Inhibits Hormone-Independent Breast Cancer Cell Growth and Down-Regulates Estrogen Receptor α and Cyclin D1

Lewis-Wambi¹,

Kim²,

Curpăn³

et al. 2011

Mol Pharmacol

116

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Bazedoxifene (BZA) is a third-generation selective estrogen receptor modulator (SERM) that has been approved for the prevention and treatment of postmenopausal osteoporosis. It has antitumor activity; however, its mechanism of action remains unclear. In the present study, we characterized the effects of BZA and several other SERMs on the proliferation of hormone-dependent MCF-7 and T47D breast cancer cells and hormone-independent MCF-7:5C and MCF-7:2A cells and examined its mechanism of action in these cells. We found that all of the SERMs inhibited the growth of MCF-7, T47D, and MCF-7:2A cells; however, only BZA and fulvestrant (FUL) inhibited the growth of hormone-independent MCF-7:5C cells. Cell cycle analysis revealed that BZA and FUL induced G 1 blockade in MCF-7:5C cells; however, BZA down-regulated cyclin D1, which was constitutively overexpressed in these cells, whereas FUL suppressed cyclin A. Further analysis revealed that small interfering RNA knockdown of cyclin D1 reduced the basal growth of MCF-7:5C cells, and it blocked the ability of BZA to induce G 1 arrest in these cells. BZA also down-regulated estrogen receptor-␣ (ER␣) protein by increasing its degradation and suppressing cyclin D1 promoter activity in MCF-7:5C cells. Finally, molecular modeling studies demonstrated that BZA bound to ER␣ in an orientation similar to raloxifene; however, a number of residues adopted different conformations in the induced-fit docking poses compared with the experimental structure of ER␣-raloxifene. Together, these findings indicate that BZA is distinct from other SERMs in its ability to inhibit hormone-independent breast cancer cell growth and to regulate ER␣ and cyclin D1 expression in resistant cells.

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“…and M.A.S. using a protocol described previously (Miller et al, 2001). All of the compounds were dissolved in 100% ethanol except for MG132, which was dissolved in dimethyl sulfoxide.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Selective Estrogen Receptor Modulator Bazedoxifene Inhibits Hormone-Independent Breast Cancer Cell Growth and Down-Regulates Estrogen Receptor α and Cyclin D1

Lewis-Wambi¹,

Kim²,

Curpăn³

et al. 2011

Mol Pharmacol

116

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“…wzięło udział 412 kobiet z osteoporozą pomenopauzalną. Grupa badana leczona różnymi dawkami podskórnymi denosumabu (14,60, 100 i 210 mg) porównywana była do grupy pacjentek leczonych w sposób klasyczny -doustnym alendronianem. Po 24 miesiącach…”

Section: Przeciwciała Monoklonalneunclassified

“…One of the latest medicines from the described group is bazedoxifene which reveals a high affinity to ERa and ERb Jednym z nowszych leków należących do opisywanej grupy jest bazedoxifen, który cechuje się wysokim powinowactwem do receptorów ERa i ERb [14]. Połączenie z receptorami estrogenowymi prowadzi to do dimeryzacji receptora a następ-nie powiązana ze składowymi odpowiedzi na estrogeny [15].…”

Section: Selective Estrogen Receptor Modulatorsunclassified

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Current pharmacotherapy of osteoporosis

Deszczyński¹,

Mitek²,

Nagraba³

et al. 2011

Arthroscopy and Joint Surgery

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SummaryMedicines currently used in the therapy of osteoporosis can be divided into two groups: antiresorptive compounds and substances having an anabolic effect on bones. Due to a wide range of drugs that can be used in the therapy of patients with osteoporosis, different targets of these medicines, and multiple reports on their effectiveness, the authors of the work decided to review the literature on new tendencies in pharmacotherapy of osteoporosis.

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Female Sex Hormones, Contraceptives, And Fertility Drugs

Ruenitz

2010

Burger's Medicinal Chemistry and Drug Discovery

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Substances that interact with estrogen or progesterone receptors have clinical applications in hormone replacement therapy, birth control, prevention and treatment of hormone‐dependent cancer, and in stimulation of fertility. This chapter describes the specific drugs in each of these categories, and their counterparts now in clinical trials or in use experimentally, with respect to mechanism of pharmacologic action, noteworthy routes of biotransformation, structure–activity relationships, and current and future prospects for therapeutic uses. The history of discovery and current understanding of the molecular endocrinologic basis of selective estrogen receptor modulators are covered, as are mechanistic, structural, and clinical aspects of drugs that interfere with estrogen biosynthesis (aromatase inhibitors). Structural and pharmacologic aspects of environmental/dietary estrogens and progestins are also included.

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Design, Synthesis, and Preclinical Characterization of Novel, Highly Selective Indole Estrogens

Cited by 131 publications

References 18 publications

The Selective Estrogen Receptor Modulator Bazedoxifene Inhibits Hormone-Independent Breast Cancer Cell Growth and Down-Regulates Estrogen Receptor α and Cyclin D1

The Selective Estrogen Receptor Modulator Bazedoxifene Inhibits Hormone-Independent Breast Cancer Cell Growth and Down-Regulates Estrogen Receptor α and Cyclin D1

Current pharmacotherapy of osteoporosis

Female Sex Hormones, Contraceptives, And Fertility Drugs

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