Structure–Activity Relationship of <i>para</i>-Carborane Selective Estrogen Receptor β Agonists

Sedlák, David; Wilson, Terry; Tjarks, Werner; Radomska, Hanna S.; Wang, Hongyan; Kolla, Jayaprakash Narayana; Leśnikowski, Zbigniew J.; Špičáková, Alena; Ali, Tarig; Ishita, Keisuke; Rakotondraibe, L. Harinantenaina; Vibhute, Sandip; Wang, Dasheng; Anzenbacher, Pavel; Bennett, Chad E.; Bartůněk, Petr; Coss, Christopher C.

doi:10.1021/acs.jmedchem.1c00555

Cited by 22 publications

(21 citation statements)

References 67 publications

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“…One reason is that for this particular indication a high degree of selectivity for ERβ over ERα would be required. Our institution recently developed a highly selective ERβ agonist: OSU-ERb-12 (16). We confirmed the selectivity of this compound using ERE-luciferase promoter assays showing ~40-fold induction upon treatment of ER overexpressing cells.…”

Section: Discussionmentioning

confidence: 55%

“…In the present study, we investigated the effects of a novel and highly selective ER selective agonist, OSU-ERb-12 (16), to inhibit preclinical models of ERα+ breast cancer and to counter endocrine and CDK4/6i resistance in vitro. We found that treatment of ERα+ breast cancer cell lines with OSU-ERb-12 caused apoptosis, induced cell cycle arrest (at S phase), as well as decreased cell proliferation, colony formation, and cell migration.…”

Section: Introductionmentioning

confidence: 99%

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Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

Datta

Willingham

Manouchehri

et al. 2022

Preprint

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Background: Among women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, resistance emergence compelling the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERβ plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERβ agonists without ERα activity has limited the exploration of ERβ activation as a strategy for ERα+ breast cancer. Methods: We measured expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307 was assessed. The specificity of the ERβ agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of the agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2 regulated genes. Results: In this study, we demonstrate the efficacy of highly selective ERβ agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERβ agonists blocked cell proliferation, migration and colony formation; and induced apoptosis and S and/or G2/M cell cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERβ agonists and ERα antagonists suggested that the efficacy of ERβ agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ER+/HER2- breast cancer samples. Conclusion: Our results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer.

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Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

Datta

Willingham

Manouchehri

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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“…OSU-ERb-12 was synthesized in the Drug Development Institute (DDI) at OSU according to the procedure outlined before ( 16 ). LY500307 was also obtained from DDI, OSU.…”

Section: Methodsmentioning

confidence: 99%

“…In the present study, we investigated the effects of a novel and highly selective ERβ-selective agonist, OSU-ERb-12 ( 16 ), to inhibit preclinical models of ERα+ breast cancer and to counter endocrine and CDK4/6i resistance in vitro . We found that treatment of ERα+ breast cancer cell lines with OSU-ERb-12 caused apoptosis, induced cell-cycle arrest (at S phase), and decreased cell proliferation, colony formation, and cell migration.…”

Section: Introductionmentioning

confidence: 99%

Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

et al. 2022

Self Cite

View full text Add to dashboard Cite

BackgroundAmong women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistance compels the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERβ plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERβ agonists without ERα activity has limited the exploration of ERβ activation as a strategy for ERα+ breast cancer.MethodsWe measured the expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307, was assessed. The specificity of the ERβ agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of ERβ agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2-regulated genes.ResultsIn this study, we demonstrate the efficacy of highly selective ERβ agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERβ agonists blocked cell proliferation, migration, and colony formation and induced apoptosis and S and/or G2/M cell-cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERβ agonists and ERα antagonists suggested that the efficacy of ERβ agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples.ConclusionOur results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer.

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“…Estrogen has important functions in cardiovascular, reproductive, skeletal, and central nervous systems. 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 E2 (17β-estradiol) and E1 (precursor of E2) were synthesized from estrone sulfate by steroid sulfatase (STS). 174 Therefore, STS could be considered as a promising target for the treatment of breast cancer.…”

Section: Applications Of Carboranes As Anticancer Ligandsmentioning

confidence: 99%

Carboranes as unique pharmacophores in antitumor medicinal chemistry

Chen

Tang

et al. 2022

Molecular Therapy - Oncolytics

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Structure–Activity Relationship of para-Carborane Selective Estrogen Receptor β Agonists

Cited by 22 publications

References 67 publications

Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

Carboranes as unique pharmacophores in antitumor medicinal chemistry

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