Estrogen receptor binding affinity and uterotrophic activity of triphenylhaloethylenes

DeSombre, Eugene R.; Mease, Ronnie C.; Sanghavl, Jigi; Singh, Tej M.; Seevers, Robert H.; Hughes, Alun

doi:10.1016/0022-4731(88)90155-0

Cited by 20 publications

(7 citation statements)

References 16 publications

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“…Ligands that demonstrate significant affinity (RBA > 10) for the ER-HBD would subsequently be evaluated for efficacy in the in vivo rat uterotrophic growth assay. 40 The products were compared to both estradiol and the unsubstituted phenylvinyl estradiol 6a using this assay in order to evaluate the effects of substituents on both the basic steroidal interactions and on the phenylvinyl group. The results of the competitive binding assays, shown in Table 2, indicated that all of the compounds retained significant affinity for the estrogen receptor.…”

Section: Resultsmentioning

confidence: 99%

“…The immature rat uterotrophic growth assay is well-established for demonstrating estrogenic and antiestrogenic responses mediated though ERR. 40 Although reporter assays have been developed more recently to define estrogenic activity, they were not available at the time to assay this series of compounds. Three compounds in each series were evaluated over a 4 log dose range (0.01-100 nmol) for their uterotrophic potency.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Evaluation of (17α,20Z)-21-(4-Substituted-phenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17β-diols as Ligands for the Estrogen Receptor-α Hormone Binding Domain: Comparison with 20E-Isomers

et al. 2005

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As part of our ongoing program to develop probes for the hormone binding domain of the estrogen receptor-alpha (ERalpha), we prepared and evaluated a series of 17alpha,Z-(4-substituted-phenyl)vinyl estradiol derivatives. The results indicated that the relative binding affinities (RBAs) at 25 degrees C for the new compounds were significant (RBA = 9-57) although less than that of estradiol (RBA = 100) or of the parent unsubstituted phenylvinyl estradiol (RBA = 66). All of the Z-compounds were full agonists in the uterotrophic assay, indicating that the ligands formed estrogen-like complexes with the estrogen receptor-alpha hormone binding domain (ERalpha-HBD). Comparison of corresponding Z- and E-4-substituted phenylvinyl ligands complexed with the ERalpha-HBD indicated small but significant differences in binding modes that may account for the differing trends seen in the structure-activity relationships for the two series.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of (17α,20Z)-21-(4-Substituted-phenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17β-diols as Ligands for the Estrogen Receptor-α Hormone Binding Domain: Comparison with 20E-Isomers

et al. 2005

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“…Immature Rat Uterotrophic Growth Assays-Selected compounds were evaluated using the uterotrophic growth assay (27). Groups of immature Sprague-Dawley female rats (10 per group for vehicle, 5 per group all others) were injected subcutaneously with 10, 50, and 250 nmol of test ligand in 100 l of vehicle (10% Cremaphor EL (Fluka Biochemicals), 88% phosphate-buffered saline, and 2% ethanol) daily for 3 consecutive days.…”

Section: Methodsmentioning

confidence: 99%

“…Immature Sprague-Dawley Rats-To test OBCP compounds in vivo, we used a rat uterotrophic assay (27), which measures estrogenic activity based on the increase in uterine weight in immature rats (43). In contrast to E2, which at a dose of 1 nmol/animal/day increased uterine weight nearly 3-fold relative to vehicle control, both OBCP-3M and OBCP-1M were very weakly uterotrophic (ϳ1.2-to 1.5-fold weight increase).…”

Section: Obcp-3m and Obcp-1m Have Very Weak Uterotrophic Activity Inmentioning

confidence: 99%

Identification of Ligands with Bicyclic Scaffolds Provides Insights into Mechanisms of Estrogen Receptor Subtype Selectivity

Hsieh

Rajan

Sharma

et al. 2006

Journal of Biological Chemistry

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Estrogen receptors ␣ (ER␣) and ␤ (ER␤) have distinct functions and differential expression in certain tissues. These differences have stimulated the search for subtype-selective ligands. Therapeutically, such ligands offer the potential to target specific tissues or pathways regulated by one receptor subtype without affecting the other. As reagents, they can be utilized to probe the physiological functions of the ER subtypes to provide information complementary to that obtained from knock-out animals. A fluorescence resonance energy transfer-based assay was used to screen a 10,000-compound chemical library for ER agonists. From the screen, we identified a family of ER␤-selective agonists whose members contain bulky oxabicyclic scaffolds in place of the planar scaffolds common to most ER ligands. These agonists are 10 -50-fold selective for ER␤ in competitive binding assays and up to 60-fold selective in transactivation assays. The weak uterotrophic activity of these ligands in immature rats and their ability to stimulate expression of an ER␤ regulated gene in human U2OS osteosarcoma cells provides more physiological evidence of their ER␤-selective nature. To provide insight into the molecular mechanisms of their activity and selectivity, we determined the crystal structures of the ER␣ ligandbinding domain (LBD) and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator complexed with the ligands OBCP-3M, OBCP-2M, and OBCP-1M. These structures illustrate how the bicyclic scaffolds of these ligands are accommodated in the flexible ligand-binding pocket of ER. A comparison of these structures with existing ER structures suggests that the ER␤ selectivity of OBCP ligands can be attributed to a combination of their interactions with Met-336 in ER␤ and Met-421 in ER␣. These bicyclic ligands show promise as lead compounds that can target ER␤. In addition, our understanding of the molecular determinants of their subtype selectivity provides a useful starting point for developing other ER modulators belonging to this relatively new structural class. Estrogen receptors ␣ (ER␣)4 and ␤ (ER␤) are ligand-inducible transcription factors that are involved in regulating cell growth, proliferation, and differentiation in various normal and cancerous tissues (1-3). Although the two subtypes of ER bind the endogenous estrogen, 17␤-estradiol (E2), with similar affinity (4), they differ in size, share modest sequence identity (47%), and are encoded by different genes (5, 6). Studies of knock-out mice have also shown that the two subtypes have distinct functions and are differentially expressed in certain tissues (1). These differences have stimulated the search for subtype-specific ligands that can elicit tissue-or cell-specific ER activity. In particular, the dominance of ER␣ expression in the breast and uterus (7) suggests that ER␤-selective ligands may offer some of the benefits of hormone replacement therapy such as a decrease in the risk of colorectal cancer (8) without increasing the risk of breast ...

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“…Fortuitously, later in 1974, I met and joined forces with Michael Welch a Professor of Radiological Sciences at Washington University Medical School in St. Louis, about a 3-h drive from the University of Illinois at Urbana-Champaign; this began a fruitful collaboration in radiopharmaceutical development that extended for nearly 38 years. At the time, other researchers interested in imaging ER in breast cancers were seeing favorable biodistribution using steroidal estrogens radioiodinated at different positions [ 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. At the time, Dr. Welch was receiving bromine-77 shipments from Los Alamos National Laboratory for other purposes (protein labeling); so, we began to prepare bromoestrogens.…”

Section: Fes a Pet Imaging Agent For Estrogen Receptors In Breastmentioning

confidence: 99%

PET Imaging Agents (FES, FFNP, and FDHT) for Estrogen, Androgen, and Progesterone Receptors to Improve Management of Breast and Prostate Cancers by Functional Imaging

Katzenellenbogen

2020

Cancers

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Many breast and prostate cancers are driven by the action of steroid hormones on their cognate receptors in primary tumors and in metastases, and endocrine therapies that inhibit hormone production or block the action of these receptors provide clinical benefit to many but not all of these cancer patients. Because it is difficult to predict which individuals will be helped by endocrine therapies and which will not, positron emission tomography (PET) imaging of estrogen receptor (ER) and progesterone receptor (PgR) in breast cancer, and androgen receptor (AR) in prostate cancer can provide useful, often functional, information on the likelihood of endocrine therapy response in individual patients. This review covers our development of three PET imaging agents, 16α-[18F]fluoroestradiol (FES) for ER, 21-[18F]fluoro-furanyl-nor-progesterone (FFNP) for PgR, and 16β-[18F]fluoro-5α-dihydrotestosterone (FDHT) for AR, and the evolution of their clinical use. For these agents, the pathway from concept through development tracks with an emerging understanding of critical performance criteria that is needed for successful PET imaging of these low-abundance receptor targets. Progress in the ongoing evaluation of what they can add to the clinical management of breast and prostate cancers reflects our increased understanding of these diseases and of optimal strategies for predicting the success of clinical endocrine therapies.

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Estrogen receptor binding affinity and uterotrophic activity of triphenylhaloethylenes

Cited by 20 publications

References 16 publications

Synthesis and Evaluation of (17α,20Z)-21-(4-Substituted-phenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17β-diols as Ligands for the Estrogen Receptor-α Hormone Binding Domain: Comparison with 20E-Isomers

Synthesis and Evaluation of (17α,20Z)-21-(4-Substituted-phenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17β-diols as Ligands for the Estrogen Receptor-α Hormone Binding Domain: Comparison with 20E-Isomers

Identification of Ligands with Bicyclic Scaffolds Provides Insights into Mechanisms of Estrogen Receptor Subtype Selectivity

PET Imaging Agents (FES, FFNP, and FDHT) for Estrogen, Androgen, and Progesterone Receptors to Improve Management of Breast and Prostate Cancers by Functional Imaging

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