The estrogen receptor alpha (ER alpha) represents a 17 beta-estradiol-inducible transcriptional regulator that initiates the RNA polymerase II-dependent transcriptional machinery, pointed for breast cancer (BC) development via either genomic direct or genomic indirect (i.e., tethered) pathway. To develop innovative ligands, structure-based (SB) three-dimensional (3-D) quantitative structure-activity relationship (QSAR) studies have been undertaken from structural data taken from partial agonists, mixed agonists/antagonists (selective estrogen receptor modulators (SERMs)), and full antagonists (selective ER alpha downregulators (SERDs)) correlated with either wild-type or mutated ER alpha receptors. SB and ligand-based (LB) alignments allow us to rule out guidelines for the SB/LB alignment of untested compounds. 3-D QSAR models for ER alpha ligands, coupled with SB/LB alignment, were revealed to be useful tools to dissect the chemical determinants for ER alpha-based anticancer activity as well as to predict their potency. The herein developed protocol procedure was verified through the design and potency prediction of 12 new coumarin-based SERMs, namely, 3DQ-1a to 3DQ-1e, that upon synthesis turned to be potent ER alpha antagonists by means of either in vitro or in vivo assays (described in the second part of this study).

Human Estrogen Receptor α Antagonists. Part 1: 3-D QSAR-Driven Rational Design of Innovative Coumarin-Related Antiestrogens as Breast Cancer Suppressants through Structure-Based and Ligand-Based Studies / Mihović, Nezrina; Tomašević, Nevena; Matić, Sanja; Mitrović, Marina M; Kostić, Danijela A; Sabatino, Manuela; Antonini, Lorenzo; Ragno, Rino; Mladenović, Milan. - In: JOURNAL OF CHEMICAL INFORMATION AND MODELING. - ISSN 1549-9596. - 61:10(2021), pp. 5028-5053. [10.1021/acs.jcim.1c00530]

Human Estrogen Receptor α Antagonists. Part 1: 3-D QSAR-Driven Rational Design of Innovative Coumarin-Related Antiestrogens as Breast Cancer Suppressants through Structure-Based and Ligand-Based Studies

Sabatino, Manuela;Antonini, Lorenzo;Ragno, Rino
;
2021

Abstract

The estrogen receptor alpha (ER alpha) represents a 17 beta-estradiol-inducible transcriptional regulator that initiates the RNA polymerase II-dependent transcriptional machinery, pointed for breast cancer (BC) development via either genomic direct or genomic indirect (i.e., tethered) pathway. To develop innovative ligands, structure-based (SB) three-dimensional (3-D) quantitative structure-activity relationship (QSAR) studies have been undertaken from structural data taken from partial agonists, mixed agonists/antagonists (selective estrogen receptor modulators (SERMs)), and full antagonists (selective ER alpha downregulators (SERDs)) correlated with either wild-type or mutated ER alpha receptors. SB and ligand-based (LB) alignments allow us to rule out guidelines for the SB/LB alignment of untested compounds. 3-D QSAR models for ER alpha ligands, coupled with SB/LB alignment, were revealed to be useful tools to dissect the chemical determinants for ER alpha-based anticancer activity as well as to predict their potency. The herein developed protocol procedure was verified through the design and potency prediction of 12 new coumarin-based SERMs, namely, 3DQ-1a to 3DQ-1e, that upon synthesis turned to be potent ER alpha antagonists by means of either in vitro or in vivo assays (described in the second part of this study).
2021
Coumarins; Estradiol; Estrogen Receptor Modulators; Female; Humans; Ligands; Quantitative Structure-Activity Relationship; Breast Neoplasms; Estrogen Receptor alpha
01 Pubblicazione su rivista::01a Articolo in rivista
Human Estrogen Receptor α Antagonists. Part 1: 3-D QSAR-Driven Rational Design of Innovative Coumarin-Related Antiestrogens as Breast Cancer Suppressants through Structure-Based and Ligand-Based Studies / Mihović, Nezrina; Tomašević, Nevena; Matić, Sanja; Mitrović, Marina M; Kostić, Danijela A; Sabatino, Manuela; Antonini, Lorenzo; Ragno, Rino; Mladenović, Milan. - In: JOURNAL OF CHEMICAL INFORMATION AND MODELING. - ISSN 1549-9596. - 61:10(2021), pp. 5028-5053. [10.1021/acs.jcim.1c00530]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1661121
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