Selective degradation of the estrogen receptor in the treatment of cancers

Wang, Zunyuan; Ma, Zhen; Shen, Zhengrong

doi:10.1016/j.jsbmb.2021.105848

Cited by 6 publications

(11 citation statements)

References 81 publications

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“…Despite many studies investigating the selective degradation of the ER for BC treatment ( Lu and Liu, 2020 ; Shagufta et al, 2020 ; Wang Z. et al, 2021 ; Kumar et al, 2021 ; Mottamal et al, 2021 ), these have mostly focused on ERα with little mention of ERβ. Our study in elaborating on the molecular characteristics and mechanism of action of the Cyclopi a extracts has in contrast explicitly evaluated selectively in terms of ER subtype levels.…”

Section: Discussionmentioning

confidence: 99%

Cyclopia extracts act as selective estrogen receptor subtype downregulators in estrogen receptor positive breast cancer cell lines: Comparison to standard of care breast cancer endocrine therapies and a selective estrogen receptor agonist and antagonist

Olayoku

Verhoog²,

Louw³

2023

Front. Pharmacol.

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Breast cancer is the most diagnosed type of cancer amongst women in economically developing countries and globally. Most breast cancers express estrogen receptor alpha (ERα) and are categorized as positive (ER+) breast cancer. Endocrine therapies such as, selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and selective estrogen receptor downregulators (SERDs) are used to treat ER+ breast cancer. However, despite their effectiveness, severe side-effects and resistance are associated with these endocrine therapies. Thus, it would be highly beneficial to develop breast cancer drugs that are as effective as current therapies, but less toxic with fewer side effects, and less likely to induce resistance. Extracts of Cyclopia species, an indigenous South African fynbos plant, have been shown to possess phenolic compounds that exhibit phytoestrogenic and chemopreventive activities against breast cancer development and progression. In the current study, three well characterized Cyclopia extracts, SM6Met, cup of tea (CoT) and P104, were examined for their abilities to modulate the levels of the estrogen receptor subtypes, estrogen receptor alpha and estrogen receptor beta (ERβ), which have been recognized as crucial to breast cancer prognosis and treatment. We showed that the Cyclopia subternata Vogel (C. subternata Vogel) extracts, SM6Met and cup of tea, but not the C. genistoides extract, P104, reduced estrogen receptor alpha protein levels while elevating estrogen receptor beta protein levels, thereby reducing the ERα:ERβ ratio in a similar manner as standard of care breast cancer endocrine therapies such as fulvestrant (selective estrogen receptor downregulator) and 4-hydroxytamoxifen (elective estrogen receptor modulator). Estrogen receptor alpha expression enhances the proliferation of breast cancer cells while estrogen receptor beta inhibits the proliferative activities of estrogen receptor alpha. We also showed that in terms of the molecular mechanisms involved all the Cyclopia extracts regulated estrogen receptor alpha and estrogen receptor beta protein levels through both transcriptional and translational, and proteasomal degradation mechanisms. Therefore, from our findings, we proffer that the C. subternata Vogel extracts, SM6Met and cup of tea, but not the C. genistoides extract, P104, selectively modulate estrogen receptor subtypes levels in a manner that generally supports inhibition of breast cancer proliferation, thereby demonstrating attributes that could be explored as potential therapeutic agents for breast cancer.

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Section: Discussionmentioning

confidence: 99%

Cyclopia extracts act as selective estrogen receptor subtype downregulators in estrogen receptor positive breast cancer cell lines: Comparison to standard of care breast cancer endocrine therapies and a selective estrogen receptor agonist and antagonist

Olayoku

Verhoog²,

Louw³

2023

Front. Pharmacol.

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“…Scheme (2): Mechanism of synthesis (ZA) compound (23,24) Scheme (3): Schiff base Mechanism of reaction (25) The FT-IR spectrum of compound (ZA) in figure showed appearance of the broad band of NH stretching of primary amine at 3423.23-3340.71 cm -1 .The 1 H -NMR spectra of compound ZA showed the appearance of (s, NH 2 ) at 5.40 (δ, ppm), as shown in figure (1)(2)(3)(4)(5)(6)(7)(8). 13 C-NMR spectra show no band for C=N as shown in figure (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). The FT-IR spectrum of compound (ZA1) showed the appearance of 1620.21 cm -1 for (C=N stretching of imine) as shown in figure (1)(2) .The 1 H-NMR spectra of compound (ZA1) showed the appearance of (s, CH of CH=N) at 8.94 (δ, ppm) as shown in figure (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

Section: Synthetic Route Strategymentioning

confidence: 95%

“…Its agonist impact in the uterus, on the other hand, may cause endometrial changes such as polyps, cancer, hyperplasia, and uterine sarcoma (9,10) . Fulvestrant, a selective estrogen receptor down regulator, has an anti-estrogen effect but appears to have a low bioavailability (11) . Problems related to hormonal managements of ER-α positive breast cancer nowadays being most important concern ,therefore new analogues candidate is important for prevention unwanted symptoms and drug related resistance (12) .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, ADME Study and Anti-proliferative evaluation against MCF-7 breast cancer cell line of new analog of a 4-aminophenyl quinazolinone derivative

Zainab A. Jabbar,

Monther F. Mahdi,

Basma M.Abd Razik

2023

AJPS

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New series of 4-aminophenyl quinazolinone attached to an aromatic aldehyde moiety has been designed. Compound (ZA) was synthesized by a reaction of benzene-1,4-diamine with 2-aminobenzoic acid. The reaction between (ZA) intermediate and different substituted aromatic aldehydes (R1- R6) is considered one of the most common chemical reactions for the synthesis of imine compounds (Schiff bases) to produce compound (ZA1-ZA6). FTIR, 1H-NMR, and 13C-NMR have been used to confirm the chemical structures of various substances. MTT assay was used to assess in vitro anti-proliferative action for estrogen receptor alpha. The anti-proliferative study discovered a dose-dependent effect on cell proliferation in breast cancer (MCF-7) with inhibitory concentration In comparison to the reference medication tamoxifen (IC50 of 133.4µg\mL), IC50 of the compounds (ZA1, ZA2, ZA3) was 0.07964, 57.43 & 0.002717 µg\mL, respectively at 72 hours on same cell line mentioned above, that also signifies that compound ZA1 has a significantly greater effect on this cell line type

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“…This results in potentially incomplete receptor blockade and limits optimal therapeutic efficacy. [7][8][9] Consequently, novel oral SERDs, for example, GW5638, its active metabolite GW7604, AZD 9496, and GDC 0810 (Figure 1) have been designed to overcome those biopharmaceutical limitations and to cause more complete removal of ERα. [9,10] Although already authorized drugs show initial efficacy, prolonged antihormonal treatment often fails due to the development of resistance.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9] Consequently, novel oral SERDs, for example, GW5638, its active metabolite GW7604, AZD 9496, and GDC 0810 (Figure 1) have been designed to overcome those biopharmaceutical limitations and to cause more complete removal of ERα. [9,10] Although already authorized drugs show initial efficacy, prolonged antihormonal treatment often fails due to the development of resistance. [11] In the case of tamoxifen, one-third of breast cancer patients will develop recurrent cancer within 15 years of treatment.…”

Section: Introductionmentioning

confidence: 99%

Development of heterodimeric estrogen receptor alpha antagonists to target simultaneously the ligand and coactivator binding site

Hörmann,

Kalchschmid,

Grabher

et al. 2023

Archiv der Pharmazie

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One‐third of breast cancer patients will develop recurrent cancer within 15 years of endocrine treatment. Notably, tumor growth in a hormone‐refractory state still relies on the interaction between estrogen receptor alpha (ERα) and upregulated coactivators. Herein, we suggest that simultaneous targeting of the primary ligand binding site (LBS) and the coactivator binding site (CABS) at ERα represents a promising alternative therapeutic strategy to overcome mutation‐driven resistance in breast cancer. We synthesized two series of compounds that connect the LBS‐binder (E)−3‐{4‐[8‐fluoro‐4‐(4‐hydroxyphenyl)‐2,3‐dihydrobenzo[b]oxepin‐5‐yl]phenyl}acrylic acid 8 with the coactivator binding site inhibitors (CBIs) 4,6‐bis(isobutyl(methyl)amino)pyrimidine or 3‐(5‐methoxy‐1H‐benzo[d]imidazol‐2‐yl)propanoic acid via covalent linkage. The most active benzoxepine‐pyrimidine conjugate 31 showed strong inhibition of estradiol‐induced transactivation (IC50 = 18.2 nM (ERα) and 61.7 nM (ERβ)) in a luciferase reporter gene assay as well as high antiproliferative effects in MCF‐7 (IC50 = 65.9 nM) and tamoxifen‐resistant MCF‐7/TamR (IC50 = 88.9 nM) breast cancer cells. All heterodimers exhibited two‐ to sevenfold higher antagonism at ERα (compared with ERβ) and were superior to the acrylic acid precursor 8 in terms of ER antagonism and antiproliferative activity. It was demonstrated on the example of 31 that the compounds did not influence the ERα content in MCF‐7 cells and therefore act as pure antiestrogens without downregulating potency. Possible interactions of the CBI at the receptor surface, which enhanced the biological activities, were evaluated using molecular docking studies.

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Selective degradation of the estrogen receptor in the treatment of cancers

Cited by 6 publications

References 81 publications

Cyclopia extracts act as selective estrogen receptor subtype downregulators in estrogen receptor positive breast cancer cell lines: Comparison to standard of care breast cancer endocrine therapies and a selective estrogen receptor agonist and antagonist

Cyclopia extracts act as selective estrogen receptor subtype downregulators in estrogen receptor positive breast cancer cell lines: Comparison to standard of care breast cancer endocrine therapies and a selective estrogen receptor agonist and antagonist

Synthesis, Characterization, ADME Study and Anti-proliferative evaluation against MCF-7 breast cancer cell line of new analog of a 4-aminophenyl quinazolinone derivative

Development of heterodimeric estrogen receptor alpha antagonists to target simultaneously the ligand and coactivator binding site

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