Structure-Based Approach for the Discovery of Novel Selective Estrogen Receptor Modulators

Rosano, Camillo; Stec-Martyna, Emilia; Lappano, Rosamaria

doi:10.2174/092986711795029645

Cited by 15 publications

(11 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The subsets of ER and ER specific agonists can be used to further define targets in other pathologic states [211][212][213][214]. Finally, we must embrace the molecular biology of coactivator/corepressor action in the molecular pharmacology drug discovery process [101,211,213,214]. Forty years ago it would have been impossible to achieve the current clinical advances without laboratory findings to transform an orphan drug group the "nonsteroidal antiestrogens" [16] into the SERMs [2, 23].…”

Section: Discussionmentioning

confidence: 99%

A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

Jordan¹

2013

View full text Add to dashboard Cite

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATEJune PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Georgetown University PERFORMING ORGANIZATION REPORT NUMBERWashington, DC 20057-0004 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe purpose of the CoE is to discover the molecular mechanisms and the modulation estrogen-induced apoptosis. The laboratory research project is focused on genomics and proteomics with a current focus on molecular interrogation to decipher mechanisms that may be applied to aid patient treatment. In parallel, but not supported by the CoE, is a pilot clinical study of estrogen-induced apoptosis in patients with metastatic breast cancer, that have had repeated cycles of successful antihormone therapy, but have subsequently failed and relapsed. A new low dose protocol is being completed. The molecular pharmacology laboratory of the Principle Investigator (PI) is advancing in all areas originally designated in the grant, e.g. a description of the time dependent changes in estrogen-responsive growth and apoptosis in model cell lines, an evaluation and description of the early proteomic pathways associated with estrogen-induced apoptosis dependent on the estrogen receptor (ER) co-activator AIB1 (SRC-3), the critical importance of the shape of the ER complex, the mechanism of c-Src activity that mediates apoptosis and the genomic spectrum of our endocrine resistant cell lines to define cell sensitivity to estrogen-induced apoptosis. We have discovered and described all the stages of the development of estrogen induced apoptosis through the (mitochondrial) pathway that becomes reinforced by the extrinsic (death receptor) pathway. We have correlated rises in reactive oxygen species (ROS) with intrinsic apoptosis and through RNAseq analysis, identified AP-1 (cFos and cJun) as the critical mediators for estrogen-induced apoptosis. SUBJECT TERMS-Gene expression micr...

show abstract

Section: Discussionmentioning

confidence: 99%

A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

Jordan¹

2013

View full text Add to dashboard Cite

show abstract

“…The two cysteine clusters allow the tetrahedral coordination of two zinc ions, the first subdomain contains a P-box (proximal box) involved in DNA recognition, while the second, structurally different from the first, contains a D-box (distal box) responsible for DNA dependent DBD dimerization [146, 147]. The P-box amino acid sequence is identical in ERα and ERβ, as a consequence ERα and ERβ bind to EREs with similar specificity and affinity [149]. The D region of ERs is the hinge domain.…”

Section: Molecular Mechanismsmentioning

confidence: 99%

“…To date, the atomic coordinates of more than 90 complexes with different ligands are deposited within the Protein Data Bank (PDB). Furthermore, different modeling studies have contributed to the identification of novel natural and/or synthetic ligands for ERα [149, 156, 157]. In broad terms, the ERα binding site is composed of a predominantly hydrophobic pocket where the ligand binds, as described previously for the ERα:E2 complex.…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Combating Malaria with Plant Molecules: A Brief Update

Negi¹,

Gupta²,

Hamid

2013

CMC

View full text Add to dashboard Cite

Observations on the role of ovarian hormones in breast cancer growth, as well as interest in contraception, stimulated research into the biology of estrogens. The identification of the classical receptors ERα and ERβ and the transmembrane receptor GPER and the resolution of the structure of the ligand bound to its receptor established the principal molecular mechanisms of estrogen action. The presence of estrogen-like compounds in many plants used in traditional medicine or ingested as food ingredients, phytoestrogens, as well as the estrogenic activities of many industrial pollutants and pesticides, xenoestrogens, have prompted investigations into their role in human health. Phyto- and xenoestrogens bind to the estrogen receptors with a lower affinity than the endogenous estrogens and can compete or substitute the hormone. Xenoestrogens, which accumulate in the body throughout life, are believed to increase breast cancer risk, especially in cases of prenatal and prepuberal exposure whereas the role of phytoestrogens is still a matter of debate. At present, the application of phytoestrogens appears to be limited to the treatment of post-menopausal symptoms in women where the production of endogenous estrogens has ceased. In this review we discuss chemistry, structure and classification, estrogen signaling and the consequences of the interactions of estrogens, phytoestrogens and xenoestrogens with their receptors, the complex interactions of endogenous and exogenous ligands, the evaluation of the health risks related to xenoestrogens, and the perspectives toward the synthesis of potent third generation selective estrogen receptor modulators (SERMs).

show abstract

“…Cross-linking reactions combined with mass spectrometry can be used in rapid detection of interacting domains of proteins[16]. Further development of cleavable and non-cleavable cross-linkers of various lengths that target specific chemical groups, advancement in high-throughput crystallography[17], and mass spectrometry of proteins and peptides allowed a much broader application of cross-linking to address questions related to protein-protein interaction, changes in three-dimensional structures etc. [18].…”

Section: Introductionmentioning

confidence: 99%

Elucidating protein inter- and intramolecular interacting domains using chemical cross-linking and matrix-assisted laser desorption ionization–time of flight/time of flight mass spectrometry

Pottiez

Ciborowski

2012

Analytical Biochemistry

View full text Add to dashboard Cite

Among many methods used to investigate proteins/protein interactions, chemical cross-linking combined with mass spectrometry remains a vital experimental approach. Mapping peptides modified by cross-linker provides clues about proteins’ interacting domains. One complication is that such modification may result from intra- but not intermolecular interactions. Therefore, for overall data interpretation, a combination of results from various platforms is necessary. It is postulated that the secretory isoform of gelsolin regulates several biological processes through interactions with proteins such as actin, fibronectin, vitamin D binding protein and unidentified receptors on the surface of eukaryotic; it also has been shown to self-assemble eventually leading to the formation of homo-multimers. As such, it is an excellent model for this study. We used four cross-linkers with arm length ranging from 7.7Å to 21.7Å and MALDI-TOF/TOF mass spectrometry as the analytical platform. Results of this study show that MALDI based mass spectrometry generates high quality data to show lysine residues modified by cross-linkers and combined with existing data based on crystallography (Protein Data Bank, PDB) can be used to discriminate between inter- and intra-molecular linking.

show abstract

Structure-Based Approach for the Discovery of Novel Selective Estrogen Receptor Modulators

Cited by 15 publications

References 65 publications

A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

Combating Malaria with Plant Molecules: A Brief Update

Elucidating protein inter- and intramolecular interacting domains using chemical cross-linking and matrix-assisted laser desorption ionization–time of flight/time of flight mass spectrometry

Contact Info

Product

Resources

About