Molecular Mechanism of Action at Estrogen Receptor α of a New Clinically Relevant Antiestrogen (GW7604) Related to Tamoxifen**This work was supported by NIH CA-56143 (to V.C.J.); Fundaçao Coordenaçao de Aperfeiçoamento de Pessoal de Nível Superior, (CAPES) Scholarship, Brazil (to R.D.); the U.S. Army Medical Research and Material Command Breast Cancer Research Program, DAMD17–96-16169 (to H.L.); the generosity of the Lynn Sage Breast Cancer Research Foundation of Northwestern Memorial Hospital; and the

Bentrem, David J.; Dardes, Rita C.; Liu, H.; Macgregor-Schafer, J.; Zapf, James; Jordan, V. Craig

doi:10.1210/endo.142.2.7932

Cited by 70 publications

(13 citation statements)

References 32 publications

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“…We demonstrate that the relationship between the amine of the piperidine ring of raloxifene and the surface Asp-351 is critical to program the estrogenic/antiestrogenic properties of the Ral⅐ER␣ complex. These data support and advance the body of recent information that describes the structure-function relationships of SERM⅐ER␣ complexes (24,25,33,37).…”

Section: Agonist or Antagonist Activity Of Raloxifene Was Not Attribusupporting

confidence: 83%

“…Reverse transcription-PCR for pS2 and ␤-actin were described previously (28). DNA assays were described previously (25).…”

Section: Methodsmentioning

confidence: 99%

“…We first showed that 4-OHT⅐D351G ER␣ complexes completely lost their estrogen-like properties to induce TGF␣ mRNA level, but the complexes maintained antiestrogenic properties (24). Additionally, changing the dimethylaminoethoxy side chain of 4-OHT for an allyl carboxylic acid (GW7604, Glaxo Wellcome, Durham, NJ) also resulted in a loss of estrogen-like properties for the SERM⅐ER␣ complex, but again there was retention of antiestrogenic properties (25). We proposed that the carboxylic acid of GW7604 repelled Asp-351, thereby disrupting the surface charge to prevent coactivator binding (25).…”

mentioning

confidence: 99%

“…Based on the principles established for the 4-OHT⅐ER␣ complex (24,25) and crystallographic structures of antiestrogenbound LBD of ER␣ (19,20), we address the structure-function relationships of the Ral⅐ER␣ complex in this study. We have tested the hypothesis that a surface-negative charge at amino acid 351 is necessary for the transcription of TGF␣ by replacing the aspartic acid with the longer glutamic acid in the Ral⅐ER␣ complex.…”

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confidence: 99%

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Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

Liu¹,

Park²,

Bentrem³

et al. 2002

Journal of Biological Chemistry

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Amino acid Asp-351 in the ligand binding domain of estrogen receptor ␣ (ER␣) plays an important role in regulating the estrogen-like activity of selective estrogen receptor modulator-ER␣ complexes. 4-Hydroxytamoxifen is a full agonist at a transforming growth factor ␣ target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with the wild-type ER␣. In contrast, raloxifene (Ral), which is also a selective estrogen receptor modulator, is a complete antiestrogen in this system. Because D351G ER␣ allosterically silences activation function-1 activity in the 4-hydroxytamoxifen-ER␣ complex with the complete loss of estrogenlike activity, we examined the converse interaction of amino acid 351 and the piperidine ring of the antiestrogen side chain of raloxifene to enhance estrogen-like action. MDA-MB-231 cells were either transiently or stably transfected with Asp-351 (the wild type), D351E, D351Y, or D351F ER␣ expression vectors. Profound differences in the agonist and antagonist actions of Ral⅐ER␣ complexes were noted only in stable transfectants. The agonist activity of the Ral⅐ER␣ complex was enhanced with D351E and D351Y ER␣, but raloxifene lost its agonist activity with D351F ER␣. The distance between the piperidine nitrogen of raloxifene and the negative charge of amino acid 351 was critical for estrogen-like actions. The role of the piperidine ring in neutralizing Asp-351 was addressed using compound R1h, a raloxifene derivative replacing the nitrogen on its piperidine ring with a carbon to form cyclohexane. The derivative was a potent agonist with wild type ER␣. These results support the concept that the side chain of raloxifene shields and neutralizes the Asp-351 to produce an antiestrogenic ER␣ complex. Alteration of either the side chain or its relationship with the negative charge at amino acid 351 controls the estrogen-like action at activating function 2b of the selective estrogen receptor modulator ER␣ complex.Raloxifene (Ral) 1 (see Fig. 1) is a polyhydroxyphenyl benzothiophene antiestrogen that has low estrogen agonist activity in the rodent uterus (1). The compound originally referred to as Ly156758 or keoxifene was abandoned for development as a treatment for breast cancer (2), because its bioavailability was less than 2% administered dose (3). However, the recognition that raloxifene maintains bone density (4, 5) and inhibits mammary carcinogenesis in the rat (6, 7) illustrates the concept of selective estrogen receptor modulation. Raloxifene is used for the prevention of osteoporosis in postmenopausal women (8), and treatment is associated with a reduced incidence of breast cancer (9).Tamoxifen is the prototype selective estrogen receptor modulator (SERM) that is used clinically for the treatment and prevention of breast cancer (10, 11) with the ability to maintain bone density in postmenopausal women (12). However, tamoxifen therapy is also associated with estrogen-like effects in the uterus with an increased incidence of endometrial cancer (13). Raloxifene is currently being ...

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Section: Agonist or Antagonist Activity Of Raloxifene Was Not Attribusupporting

confidence: 83%

“…Reverse transcription-PCR for pS2 and ␤-actin were described previously (28). DNA assays were described previously (25).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

Liu¹,

Park²,

Bentrem³

et al. 2002

Journal of Biological Chemistry

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“…However there was a repulsion of the carboxylic acid of GW7604 with the same amino acid. It is proposed that GW7604 is less estrogenic than 4-OH tamoxifen in the ER-α because it disturbs the charge environment at Asp 351 [143]. In a study by Willson et al the molecular mechanism of action of GW5638 was investigated [144].…”

Section: Carboxylic Acid Derivativesmentioning

confidence: 99%

Advances in the Science of Estrogen Receptor Modulation

Mj¹,

Dg²

2003

CMC

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This work details recent advances in the science of estrogen receptor (ER) modulation, with emphasis on the discovery of novel ligands for the ER ligand binding domain (LBD). A detailed examination of structural studies of the ERs is presented with analysis of the impact of such works on contemporary ligand design and the molecular pharmacology of the ER. The various classes of ER modulators are discussed on the basis of stuctural similarities including selective estrogen receptor modulators (SERMs) and 'pure' non-steroidal antiestrogens. Additionally we review the emergence of a novel selective class of modulator which we have termed the selective estrogen receptor subtype modulators (SERSMs) and, in a departure from LBD strategies we examine the discovery of novel peptide inhibitors of the ER which inhibit transcriptional activiation of agonist liganded receptor through interaction with coactivator recruitment proteins, and offer unique insight to the mechanism of action of all classes of ER modulators. Through examination of patent and classical literature we present a thorough and informative cross-section of the contemporary state of the art in this exciting field of pharmaceutical research.

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Estrogen Receptor Modulators

Rosales

Gutgesell

Ratia

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The estrogen receptor (ER) has historically played and continues to play a prominent role in drug discovery as a target for medicinal chemists. The first targeted cancer therapy was directed at ERα and the first clinical drug that is a proteolysis targeting small molecule is also an ER ligand used to treat metastatic breast cancer. The last decade has been described as a renaissance in the medicinal chemistry of endocrine therapy, therefore, this article focuses on design of small molecule ERα ligands for treatment of hormone‐dependent breast cancer. As our understanding of the role of ER in resistance to endocrine therapy increases, further opportunities will be presented for medicinal chemists to design therapeutic agents for metastatic disease. Beyond breast cancer, ER, whether nuclear or extranuclear remains largely unexploited as a target for small molecule drug design, which is partly explained by the complexity of the underlying biology and partly by the cooling influence of the initial Women's Health Initiative outcomes on estrogen replacement therapy. Old and new concepts of ligand binding and signal transduction by ER are presented to stimulate the interests of medicinal chemists; accompanied by a catalogue of newer small molecule ligands reported in the literature and their interactions with ER.

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Cited by 70 publications

References 32 publications

Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

Advances in the Science of Estrogen Receptor Modulation

Estrogen Receptor Modulators

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