Synthesis and biological evaluation of 11′ imidazolyl antiprogestins and mesoprogestins

Nickisch, Klaus; Elger, W.; Santhamma, Bindu; Garfield, Robert E.; Killeen, Zachary; Amelkina, Olga; Schneider, Birgitt; Meister, Reinhard

doi:10.1016/j.steroids.2014.08.017

Cited by 5 publications

(10 citation statements)

References 20 publications

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“…Our in vivo study revealed that EC313 blocked the estrogenicity of E2 on uterus and mammary gland proliferation including ductal length, terminal end bud development and induced apoptosis. This results were matched with our previous findings classified EC313 as a mesoprogestin [ 38 ]. The context dependent progesterone action might help to explain the observed effects of EC313 on T47D breast cancer cells and benign mouse mammary glands.…”

Section: Discussionsupporting

confidence: 93%

“…These in vitro data correlate with in vivo data in guinea pigs that characterize EC-317, as a very pure antagonist and EC313 as mesoprogestin with strong partial agonistic activity [ 31 ]. In the case EC312, the receptor binding studies does not correlate with our previously published in vivo studies in guinea pigs [ 38 ]. This might be due to the difference in binding preference as seen in in silico studies ( S1 Text , S1 Fig , S1 Table ) or preference in the recruitment of co-factor/co-repressor and exerting non-genomic action.…”

Section: Resultsmentioning

confidence: 61%

“…Antiglucocorticoid activity was determined using select screen assay system (Invitrogen-Life Technologies) as described in our previously published studies [ 21 , 22 , 31 ].…”

Section: Methodsmentioning

confidence: 99%

“…However, all of these compounds belong to the class of pure progesterone receptor antagonists that lack partial agonistic activity. Such compounds are therefore not suited for a combination therapy with estrogens because this would lead to unopposed estrogenicity in the endometrium, leading to conditions such as hyperplasia or endometrial cancer [ 21 , 22 ]. Patients who received up to four, 3-month long, courses of Ulipristal acetate (UPA) 10 mg daily, immediately followed by 10-day double-blind treatment with NETA (10 mg daily) or placebo, effectively controlled bleeding and fibroids shrunk in patients with symptomatic fibroids.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Combination of Estradiol with Selective Progesterone Receptor Modulators (SPRMs) on Human Breast Cancer Cells In Vitro and In Vivo

et al. 2016

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Use of estrogen or estrogen / progestin combination was an approved regimen for menopausal hormonal therapy (MHT). However, more recent patient-centered studies revealed an increase in the incidence of breast cancer in women receiving menopausal hormone therapy with estrogen plus progestin rather than estrogen alone. Tissue selective estrogen complex (TSEC) has been proposed to eliminate the progesterone component of MHT with supporting evidences. Based on our previous studies it is evident that SPRMs have a safer profile on endometrium in preventing unopposed estrogenicity. We hypothesized that a combination of estradiol (E2) with selective progesterone receptor modulator (SPRM) to exert a safer profile on endometrium will also reduce mammary gland proliferation and could be used to prevent breast cancer when used in MHT. In order to test our hypothesis, we compared the estradiol alone or in combination with our novel SPRMs, EC312 and EC313. The compounds were effectively controlled E2 mediated cell proliferation and induced apoptosis in T47D breast cancer cells. The observed effects were found comparable that of BZD in vitro. The effects of SPRMs were confirmed by receptor binding studies as well as gene and protein expression studies. Proliferation markers were found downregulated with EC312/313 treatment in vitro and reduced E2 induced mammary gland proliferation, evidenced as reduced ductal branching and terminal end bud growth in vivo. These data supporting our hypothesis that E2+EC312/EC313 blocked the estrogen action may provide basic rationale to further test the clinical efficacy of SPRMs to prevent breast cancer incidence in postmenopausal women undergoing MHT.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 61%

“…Antiglucocorticoid activity was determined using select screen assay system (Invitrogen-Life Technologies) as described in our previously published studies [ 21 , 22 , 31 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Combination of Estradiol with Selective Progesterone Receptor Modulators (SPRMs) on Human Breast Cancer Cells In Vitro and In Vivo

et al. 2016

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“…To this end, we performed genomic analysis in T47D xenografts treated with various SERMs (tamoxifen, bazedoxifene, raloxifene), selective ER degrader fluvestrant, PR agonists (progesterone, medroxy progesterone acetate (MPA) or synthetic progestin R5020), PR antagonists CDB4124 and CDB4453, and SPRM EC313 (Figure 3A ). CDB4124 and CDB4453 are highly-selective PR ligands that antagonize R5020-induced transcriptional activity and proliferation of T47D cells [ 45 – 48 ]. In contrast, EC313 is a SPRM engineered on a PR agonist molecular backbone [ 47 , 48 ].…”

Section: Resultsmentioning

confidence: 99%

Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling

et al. 2017

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Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic.

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New molecular entities and structure–activity relationships of drugs designed by the natural product derivatization method from 2010 to 2018

Cui

Bian

et al. 2021

Studies in Natural Products Chemistry

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Synthesis and biological evaluation of 11′ imidazolyl antiprogestins and mesoprogestins

Cited by 5 publications

References 20 publications

Effects of Combination of Estradiol with Selective Progesterone Receptor Modulators (SPRMs) on Human Breast Cancer Cells In Vitro and In Vivo

Effects of Combination of Estradiol with Selective Progesterone Receptor Modulators (SPRMs) on Human Breast Cancer Cells In Vitro and In Vivo

Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling

New molecular entities and structure–activity relationships of drugs designed by the natural product derivatization method from 2010 to 2018

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