Scholars@Duke
John David Norris

John David Norris

Associate Research Professor in Pharmacology & Cancer Biology
Pharmacology & Cancer Biology
norri003@duke.edu
Duke Box 3813, Durham, NC 27710
Research Drive, LSRC Bldg, C251, Durham, NC 27710

Selected Publications

Structural Determinants of the Binding and Activation of Estrogen Receptor α by Phenolic Thieno[2,3-d]pyrimidines

Journal Article Helvetica Chimica Acta · September 1, 2023 Synthetic, structural, and computational approaches were used to solve the puzzle as to how a phenolic nonsteroidal estrogen 1 with only a single H-bond to its receptor was more potent than an isomer 2 which formed an intricate network of H-bonds. Synthesi ... Full text Cite

PPAR agonists attenuate lenalidomide's anti-myeloma activity in vitro and in vivo.

Journal Article Cancer Lett · October 1, 2022 Many patients with multiple myeloma (MM) have comorbidities and are treated with PPAR agonists. Immunomodulatory agents (IMiDs) are the cornerstones for MM therapy. Currently, little is known about how co-administration of PPAR agonists impacts lenalidomid ... Full text Link to item Cite

A New Chemotype of Chemically Tractable Nonsteroidal Estrogens Based on a Thieno[2,3-d]pyrimidine Core.

Journal Article ACS Med Chem Lett · July 14, 2022 Despite continued interest in the development of nonsteroidal estrogens and antiestrogens, there are only a few chemotypes of estrogen receptor ligands. Using targeted screening in a ligand sensing assay, we identified a phenolic thieno[2,3-d]pyrimidine wi ... Full text Link to item Cite

The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor.

Journal Article Mol Cancer Ther · July 2020 The estrogen receptor (ER/ESR1) is expressed in a majority of breast cancers and drugs that inhibit ER signaling are the cornerstone of breast cancer pharmacotherapy. Currently, aromatase inhibitors are the frontline endocrine interventions of choice altho ... Full text Link to item Cite

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer.

Journal Article Breast Cancer Res Treat · April 2020 PURPOSE: The combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of ... Full text Link to item Cite

Correction to: Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.

Journal Article Breast Cancer Res Treat · February 2020 The article Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy, written by Suzanne E. Wardell, Alexander P. Yllanes, ... Full text Link to item Cite

Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.

Journal Article Breast Cancer Res Treat · January 2020 PURPOSE: Fulvestrant is a selective estrogen receptor downregulator (SERD) that is approved for first- or second-line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3-kinase inhibitors for the treatment of meta ... Full text Link to item Cite

The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.

Journal Article Cell Rep · October 22, 2019 Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly in ... Full text Link to item Cite

HOXB13 interaction with MEIS1 modifies proliferation and gene expression in prostate cancer.

Journal Article Prostate · March 2019 BACKGROUND: The recurrent p.Gly84Glu germline mutation (G84E) in HOXB13 is consistently associated with prostate cancer (PCa), although the mechanisms underlying such linkage remain elusive. The majority of the PCa-associated HOXB13 mutations identified ar ... Full text Link to item Cite

Targeting mutant estrogen receptors.

Journal Article Elife · January 16, 2019 A drug used in hormone replacement therapy can target estrogen receptors that have become resistant to breast cancer treatments. ... Full text Link to item Cite

Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.

Journal Article Cancer Discov · September 2018 Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast c ... Full text Link to item Cite

Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.

Journal Article J Med Chem · April 12, 2018 In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine thera ... Full text Link to item Cite

Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery.

Journal Article Cancer Cell · February 12, 2018 In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevan ... Full text Open Access Link to item Cite

CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC.

Journal Article Mol Cancer Res · June 2017 Resistance to second-generation androgen receptor (AR) antagonists and CYP17 inhibitors in patients with castration-resistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to AR overexpr ... Full text Link to item Cite

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer.

Journal Article J Clin Invest · June 1, 2017 The clinical utility of inhibiting cytochrome P450 17A1 (CYP17), a cytochrome p450 enzyme that is required for the production of androgens, has been exemplified by the approval of abiraterone for the treatment of castration-resistant prostate cancer (CRPC) ... Full text Link to item Cite

Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.

Journal Article J Med Chem · April 13, 2017 Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimizatio ... Full text Link to item Cite

MMTV-PyMT and Derived Met-1 Mouse Mammary Tumor Cells as Models for Studying the Role of the Androgen Receptor in Triple-Negative Breast Cancer Progression.

Journal Article Horm Cancer · April 2017 Triple-negative breast cancer (TNBC) has a faster rate of metastasis compared to other breast cancer subtypes, and no effective targeted therapies are currently FDA-approved. Recent data indicate that the androgen receptor (AR) promotes tumor survival and ... Full text Link to item Cite

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer.

Journal Article Nat Chem Biol · October 2016 Clinical resistance to the second-generation antiandrogen enzalutamide in castration-resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights an unmet medical need for next-generation antagonists. We have i ... Full text Link to item Cite

Abstract P3-14-04: Effects of the dual selective CYP17 lyase inhibitor and androgen receptor (AR) antagonist, VT-464, on AR+ and ER+ tumor models in vitro and in vivo

Conference Cancer Research · February 15, 2016 AbstractVT-464 is a lyase-selective inhibitor of the dual-activity CYP17A1 enzyme that is required for the synthesis of androgens and estrogens in the gonads, adrenals, and tumors. In addition to its role as ... Full text Cite

Structural Determinants of the Binding and Activation of Estrogen Receptor α by Phenolic Thieno[2,3-d]pyrimidines

Journal Article Helvetica Chimica Acta · September 1, 2023 Synthetic, structural, and computational approaches were used to solve the puzzle as to how a phenolic nonsteroidal estrogen 1 with only a single H-bond to its receptor was more potent than an isomer 2 which formed an intricate network of H-bonds. Synthesi ... Full text Cite

PPAR agonists attenuate lenalidomide's anti-myeloma activity in vitro and in vivo.

Journal Article Cancer Lett · October 1, 2022 Many patients with multiple myeloma (MM) have comorbidities and are treated with PPAR agonists. Immunomodulatory agents (IMiDs) are the cornerstones for MM therapy. Currently, little is known about how co-administration of PPAR agonists impacts lenalidomid ... Full text Link to item Cite

A New Chemotype of Chemically Tractable Nonsteroidal Estrogens Based on a Thieno[2,3-d]pyrimidine Core.

Journal Article ACS Med Chem Lett · July 14, 2022 Despite continued interest in the development of nonsteroidal estrogens and antiestrogens, there are only a few chemotypes of estrogen receptor ligands. Using targeted screening in a ligand sensing assay, we identified a phenolic thieno[2,3-d]pyrimidine wi ... Full text Link to item Cite

The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor.

Journal Article Mol Cancer Ther · July 2020 The estrogen receptor (ER/ESR1) is expressed in a majority of breast cancers and drugs that inhibit ER signaling are the cornerstone of breast cancer pharmacotherapy. Currently, aromatase inhibitors are the frontline endocrine interventions of choice altho ... Full text Link to item Cite

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer.

Journal Article Breast Cancer Res Treat · April 2020 PURPOSE: The combination of targeting the CDK4/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of ... Full text Link to item Cite

Correction to: Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.

Journal Article Breast Cancer Res Treat · February 2020 The article Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy, written by Suzanne E. Wardell, Alexander P. Yllanes, ... Full text Link to item Cite

Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.

Journal Article Breast Cancer Res Treat · January 2020 PURPOSE: Fulvestrant is a selective estrogen receptor downregulator (SERD) that is approved for first- or second-line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3-kinase inhibitors for the treatment of meta ... Full text Link to item Cite

The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.

Journal Article Cell Rep · October 22, 2019 Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly in ... Full text Link to item Cite

HOXB13 interaction with MEIS1 modifies proliferation and gene expression in prostate cancer.

Journal Article Prostate · March 2019 BACKGROUND: The recurrent p.Gly84Glu germline mutation (G84E) in HOXB13 is consistently associated with prostate cancer (PCa), although the mechanisms underlying such linkage remain elusive. The majority of the PCa-associated HOXB13 mutations identified ar ... Full text Link to item Cite

Targeting mutant estrogen receptors.

Journal Article Elife · January 16, 2019 A drug used in hormone replacement therapy can target estrogen receptors that have become resistant to breast cancer treatments. ... Full text Link to item Cite

Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.

Journal Article Cancer Discov · September 2018 Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast c ... Full text Link to item Cite

Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.

Journal Article J Med Chem · April 12, 2018 In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine thera ... Full text Link to item Cite

Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery.

Journal Article Cancer Cell · February 12, 2018 In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevan ... Full text Open Access Link to item Cite

CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC.

Journal Article Mol Cancer Res · June 2017 Resistance to second-generation androgen receptor (AR) antagonists and CYP17 inhibitors in patients with castration-resistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to AR overexpr ... Full text Link to item Cite

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer.

Journal Article J Clin Invest · June 1, 2017 The clinical utility of inhibiting cytochrome P450 17A1 (CYP17), a cytochrome p450 enzyme that is required for the production of androgens, has been exemplified by the approval of abiraterone for the treatment of castration-resistant prostate cancer (CRPC) ... Full text Link to item Cite

Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer.

Journal Article J Med Chem · April 13, 2017 Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimizatio ... Full text Link to item Cite

MMTV-PyMT and Derived Met-1 Mouse Mammary Tumor Cells as Models for Studying the Role of the Androgen Receptor in Triple-Negative Breast Cancer Progression.

Journal Article Horm Cancer · April 2017 Triple-negative breast cancer (TNBC) has a faster rate of metastasis compared to other breast cancer subtypes, and no effective targeted therapies are currently FDA-approved. Recent data indicate that the androgen receptor (AR) promotes tumor survival and ... Full text Link to item Cite

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer.

Journal Article Nat Chem Biol · October 2016 Clinical resistance to the second-generation antiandrogen enzalutamide in castration-resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights an unmet medical need for next-generation antagonists. We have i ... Full text Link to item Cite

Abstract P3-14-04: Effects of the dual selective CYP17 lyase inhibitor and androgen receptor (AR) antagonist, VT-464, on AR+ and ER+ tumor models in vitro and in vivo

Conference Cancer Research · February 15, 2016 AbstractVT-464 is a lyase-selective inhibitor of the dual-activity CYP17A1 enzyme that is required for the synthesis of androgens and estrogens in the gonads, adrenals, and tumors. In addition to its role as ... Full text Cite

Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer.

Journal Article Clin Cancer Res · November 15, 2015 PURPOSE: Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains first-line therapy for the management of estrogen receptor (ESR1)-positive breast cancer. However, ESR1 mutations or other ligand-independent ESR1 activation mechanisms limit th ... Full text Link to item Cite

Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.

Journal Article Angew Chem Int Ed Engl · August 10, 2015 Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown ... Full text Link to item Cite

Oral Selective Estrogen Receptor Downregulators (SERDs), a Breakthrough Endocrine Therapy for Breast Cancer.

Journal Article J Med Chem · June 25, 2015 Drugs that inhibit estrogen receptor alpha (ERα) or that block the production of estrogens remain frontline interventions in the treatment and management of breast cancer at all stages. However, resistance to endocrine therapies, especially in the setting ... Full text Link to item Cite

Direct effects of the selective CYP17 lyase (L) inhibitor, VT-464, on the androgen receptor (AR) and its oral activity in an F876L tumor mouse xenograft model.

Conference Journal of Clinical Oncology · March 1, 2015 263 Background: MDV3100 inhibits binding of androgens to AR and abiraterone is known to block androgen production through CYP17 inhibition; both are effective treatments for castration-resistant prostate cancer (CRPC, yet cross-r ... Full text Cite

Obesity, cholesterol metabolism, and breast cancer pathogenesis.

Journal Article Cancer Res · September 15, 2014 Obesity and altered lipid metabolism are risk factors for breast cancer in pre- and post-menopausal women. These pathologic relationships have been attributed in part to the impact of cholesterol on the biophysical properties of cell membranes and to the i ... Full text Link to item Cite

ELF3 is a repressor of androgen receptor action in prostate cancer cells.

Journal Article Oncogene · February 13, 2014 The androgen receptor (AR) has a critical role in the development and progression of prostate cancer (PC) and is a major therapeutic target in this disease. The transcriptional activity of AR is modulated by the coregulators with which it interacts, and co ... Full text Link to item Cite

Bisphenol A affects androgen receptor function via multiple mechanisms.

Journal Article Chem Biol Interact · May 25, 2013 Bisphenol A (BPA), is a well-known endocrine disruptor compound (EDC) that affects the normal development and function of the female and male reproductive system, however the mechanisms of action remain unclear. To investigate the molecular mechanisms of h ... Full text Link to item Cite

The homeodomain protein HOXB13 regulates the cellular response to androgens.

Journal Article Mol Cell · November 13, 2009 HOXB13 is a member of the homeodomain family of sequence-specific transcription factors and, together with the androgen receptor (AR), plays a critical role in the normal development of the prostate gland. We demonstrate here that, in prostate cancer cells ... Full text Link to item Cite

Induction of Kruppel-like factor 5 expression by androgens results in increased CXCR4-dependent migration of prostate cancer cells in vitro.

Journal Article Mol Endocrinol · September 2009 Advanced prostate cancers preferentially metastasize to bone, suggesting that this tissue produces factors that provide a suitable microenvironment for prostate cancer cells. Recently, it has become clear that even in antiandrogen-resistant cancers, the an ... Full text Link to item Cite

Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists.

Journal Article Proc Natl Acad Sci U S A · July 21, 2009 The impact of ligand binding on nuclear receptor (NR) structure and the ability of target cells to distinguish between different receptor-ligand complexes are key determinants of the pharmacological activity of NR ligands. However, until relatively recentl ... Full text Link to item Cite

Differential presentation of protein interaction surfaces on the androgen receptor defines the pharmacological actions of bound ligands.

Journal Article Chem Biol · April 24, 2009 The pharmacological activity of different nuclear receptor ligands is reflected by their impact on receptor structure. Thus, we asked whether differential presentation of protein-protein interaction surfaces on the androgen receptor (AR), a surrogate assay ... Full text Link to item Cite

Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic.

Journal Article Cancer Res · September 15, 2008 Androgens, through their actions on the androgen receptor (AR), are required for the development of the prostate and contribute to the pathologic growth dysregulation observed in prostate cancers. Consequently, androgen ablation has become an essential com ... Full text Link to item Cite

Linking ligand-induced alterations in androgen receptor structure to differential gene expression: a first step in the rational design of selective androgen receptor modulators.

Journal Article Mol Endocrinol · June 2006 We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to es ... Full text Link to item Cite

Structural basis for an unexpected mode of SERM-mediated ER antagonism.

Journal Article Mol Cell · May 13, 2005 Tamoxifen is effective for the prevention and treatment of estrogen-dependent breast cancers, but is associated with an increased incidence of endometrial tumors. We report the crystal structure of the estrogen receptor alpha (ERalpha) ligand binding domai ... Full text Link to item Cite

Single-step purification of full-length human androgen receptor.

Journal Article Nuclear receptor signaling · January 2005 The full-length human androgen receptor with an N-terminal biotin acceptor peptide tag was overexpressed in Spodoptera frugiperda cells in the presence of 1 microM dihydrotestosterone. Site-specific biotinylation of BAP was achieved in vivo by co-expressio ... Full text Cite

Identification of a negative regulatory surface within estrogen receptor alpha provides evidence in support of a role for corepressors in regulating cellular responses to agonists and antagonists.

Journal Article Mol Endocrinol · August 2002 Several lines of evidence have indicated that the estrogen receptor (ER) can recruit the corepressors, nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid receptors (SMRT), to target genes in the presence of tamoxifen, sugges ... Full text Link to item Cite

Elucidation of the molecular mechanism of action of selective estrogen receptor modulators.

Journal Article Am J Cardiol · July 3, 2002 The term selective estrogen receptor modulator (SERM) describes a group of pharmaceuticals that manifest estrogen receptor (ER) agonist activity in some tissues but opposes estrogen action in others. Although the name describing this class of drugs is new, ... Full text Link to item Cite

Connections and regulation of the human estrogen receptor.

Journal Article Science · May 31, 2002 Estrogen regulates a plethora of functionally dissimilar processes in a broad range of tissues. Recent progress in the study of the molecular mechanism of action of estrogen(s) has revealed why different cells can respond to the same hormone in a different ... Full text Link to item Cite

A negative coregulator for the human ER.

Journal Article Mol Endocrinol · March 2002 Featured Publication ERalpha is a ligand-activated transcription factor and a key regulator of the processes involved in cellular proliferation and differentiation. In addition, aberrant ERalpha activity is linked to several pathological conditions including breast cancer. A c ... Full text Link to item Cite

Definition of the molecular and cellular mechanisms underlying the tissue-selective agonist/antagonist activities of selective estrogen receptor modulators.

Journal Article Recent Prog Horm Res · 2002 The term selective estrogen receptor modulators describes a group of pharmaceuticals that function as estrogen receptor (ER) agonists in some tissues but that oppose estrogen action in others. Although the name for this class of drugs has been adopted only ... Full text Link to item Cite

Capitalizing on the complexities of estrogen receptor pharmacology in the quest for the perfect SERM.

Journal Article Ann N Y Acad Sci · December 2001 The term Selective Estrogen Receptor Modulators (SERMs) has been used of late to describe a group of pharmaceuticals that manifest estrogen receptor (ER) agonist activity in some tissues, but that oppose estrogen action in others. Whereas the name describi ... Full text Link to item Cite

Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor.

Journal Article Cancer Res · April 1, 2001 Tamoxifen inhibits estrogen receptor (ER) transcriptional activity by competitively inhibiting estradiol binding and inducing conformational changes in the receptor that may prevent its interaction with coactivators. In bone, the cardiovascular system, and ... Link to item Cite

Estrogen receptor-cofactor interactions as targets for novel drug discovery.

Journal Article Ernst Schering Res Found Workshop · 2001 Featured Publication Full text Link to item Cite

Development of peptide antagonists that target estrogen receptor-cofactor interactions.

Journal Article J Steroid Biochem Mol Biol · November 30, 2000 Featured Publication We have developed a series of high-affinity peptide antagonists that inhibit the transcriptional activity of both subtypes of the human estrogen receptor (ERalpha and ERbeta). We believe that it will be possible to develop these peptides, or corresponding ... Full text Link to item Cite

Modulation of estrogen receptor-alpha transcriptional activity by the coactivator PGC-1.

Journal Article J Biol Chem · May 26, 2000 A transcriptional coactivator of the peroxisome proliferator-activated receptor-gamma (PPARgamma), PPARgamma-coactivator-1(PGC-1) interacts in a constitutive manner with the hinge domain of PPARgamma and enhances its transcriptional activity. In this study ... Full text Link to item Cite

Comparative analyses of mechanistic differences among antiestrogens.

Journal Article Endocrinology · December 1999 Antiestrogens such as tamoxifen are one of the most effective methods of treating estrogen receptor (ERalpha) positive breast cancers; however, the effectiveness of this therapy is limited by the almost universal development of resistance to the drug. If a ... Full text Link to item Cite

Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors alpha and beta.

Journal Article Mol Cell Biol · December 1999 Recruitment of transcriptional coactivators following ligand activation is a critical step in nuclear receptor-mediated target gene expression. Upon binding an agonist, the receptor undergoes a conformational change which facilitates the formation of a spe ... Full text Link to item Cite

Peptide antagonists of the human estrogen receptor.

Journal Article Science · July 30, 1999 Featured Publication Estrogen receptor alpha transcriptional activity is regulated by distinct conformational states that are the result of ligand binding. Phage display was used to identify peptides that interact specifically with either estradiol- or tamoxifen-activated estr ... Full text Link to item Cite

Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta.

Journal Article Proc Natl Acad Sci U S A · March 30, 1999 Estrogen receptor (ER) modulators produce distinct tissue-specific biological effects, but within the confines of the established models of ER action it is difficult to understand why. Previous studies have suggested that there might be a relationship betw ... Full text Link to item Cite

Potency of combined estrogenic pesticides: Synergy between synthetic oestrogens?

Journal Article Chemtracts · April 1, 1998 These studies each show that certain binary mixtures of weak, environmental estrogens act additively. The results were obtained by testing mixtures of these compounds in a variety of estrogen assays. These studies were prompted by a now retracted report th ... Cite

Enhancement of estrogen receptor transcriptional activity by the coactivator GRIP-1 highlights the role of activation function 2 in determining estrogen receptor pharmacology.

Journal Article J Biol Chem · March 20, 1998 The human estrogen receptor (ER) contains two major activation functions (AFs) responsible for its transcriptional activity. One of these, activation function 2 (AF-2), located within the hormone-binding domain (HBD), has been shown to mediate the ligand-d ... Full text Link to item Cite

The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor.

Journal Article Mol Cell Biol · March 1998 Previously, we defined a novel class of ligands for the human progesterone receptor (PR) which function as mixed agonists. These compounds induce a conformational change upon binding the receptor that is different from those induced by agonists and antagon ... Full text Link to item Cite

Dissection of the molecular mechanism of action of GW5638, a novel estrogen receptor ligand, provides insights into the role of estrogen receptor in bone.

Journal Article Endocrinology · September 1997 The estrogen receptor (ER) mixed agonists tamoxifen and raloxifene have been shown to protect against bone loss in ovariectomized rats. However, the mechanism by which these compounds manifest their activity in bone is unknown. We have used a series of in ... Full text Link to item Cite

Identification of a third autonomous activation domain within the human estrogen receptor.

Journal Article Mol Endocrinol · June 1997 Using a genetic selection system established in the yeast Saccharomyces cerevisiae, we have isolated, by random mutagenesis of the human estrogen receptor (ER), six mutants that display constitutive transcriptional activity. All of the mutants identified c ... Full text Link to item Cite

Estrogenic activity of a dieldrin/toxaphene mixture in the mouse uterus, MCF-7 human breast cancer cells, and yeast-based estrogen receptor assays: no apparent synergism.

Journal Article Endocrinology · April 1997 The estrogenic activity of dieldrin, toxaphene, and an equimolar mixture of both compounds (dieldrin/toxaphene) was investigated in the 21-day-old B6C3F1 mouse uterus, MCF-7 human breast cancer cells, and in yeast-based reporter gene assays. Treatment of t ... Full text Link to item Cite

Potency of combined estrogenic pesticides.

Journal Article Science · January 17, 1997 Full text Link to item Cite

BRCA1 expression is not directly responsive to estrogen.

Journal Article Oncogene · January 9, 1997 Expression of the breast cancer susceptibility gene, BRCA1, is induced by 17-beta estradiol (E2) in estrogen receptor containing breast cancer cell lines. Our previous studies have shown that BRCA1 transcription is also regulated with the cell cycle, reach ... Full text Link to item Cite

Identification of the sequences within the human complement 3 promoter required for estrogen responsiveness provides insight into the mechanism of tamoxifen mixed agonist activity.

Journal Article Mol Endocrinol · December 1996 The promoter of the human C3 gene has been shown to be responsive to stimulation by both estrogen and tamoxifen-activated estrogen receptor (ER) in transcriptional assays reconstituted in mammalian cells. Using a series of deletions and point mutations, we ... Full text Link to item Cite

Structure-function relationships of the complement regulatory protein, CD59.

Journal Article Blood Cells Mol Dis · 1996 CD59 (membrane inhibitor of reactive lysis, protectin) is a membrane protein whose functions include the inhibition of the insertion of the ninth component of complement into the target membrane. It belongs to a superfamily of proteins including Ly-6, elap ... Full text Link to item Cite

Identification of a new subclass of Alu DNA repeats which can function as estrogen receptor-dependent transcriptional enhancers.

Journal Article J Biol Chem · September 29, 1995 We have utilized a genetic selection system in yeast to identify novel estrogen-responsive genes within the human genome and to define the sequences in the BRCA-1 gene responsible for its estrogen responsiveness. This approach led to the identification of ... Full text Link to item Cite

Glycosyl-phosphatidylinositol anchor synthesis in paroxysmal nocturnal hemoglobinuria: partial or complete defect in an early step.

Journal Article Blood · February 1, 1994 The defect in the biosynthesis of the glycosyl-phosphatidyl inositol (GPI) anchor in paroxysmal nocturnal hemoglobinuria (PNH) appears to be in the initial steps. In biosynthetic studies using [3H]mannose, abnormal granulocytes of eight patients, and B lym ... Link to item Cite