Characterization of New Estrogen Receptor Destabilizing Compounds: Effects on Estrogen-Sensitive and Tamoxifen-Resistant Breast Cancer

Hoffmann, Jens; Bohlmann, Rolf; Heinrich, Nikolaus; Hofmeister, Helmut; Kroll, Jörg; Künzer, Hermann; Lichtner, Rosemarie B.; Nishino, Yuki; Parczyk, Karsten; Sauer, Gerhard; Gieschen, Hille; Ulbrich, Hannes-F; Schneider, Martin

doi:10.1093/jnci/djh022

Cited by 84 publications

(61 citation statements)

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“…For instance, fulvestrant analogues ZK-703 and ZK-253 (Fig. 1D) were shown to inhibit growth of ER+ xenografts, including tamoxifen-resistant tumors, more efficiently than ICI 182,780; interestingly, compound ZK-253 demonstrated increased oral bioavailability in these models (Hoffmann et al . 2004).…”

Section: Serms Vs Serds: Two Separate Classes Of Antiestrogens?mentioning

confidence: 99%

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Antiestrogens: structure-activity relationships and use in breast cancer treatment

Traboulsi

Ezzy

Gleason

et al. 2017

Journal of Molecular Endocrinology

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About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as selective estrogen receptor modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second- and third-generation AEs, however, suggests the induction of diverse ERα structural conformations, resulting in variable degrees of receptor downregulation and different patterns of systemic properties in animal models and in the clinic.

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Section: Serms Vs Serds: Two Separate Classes Of Antiestrogens?mentioning

confidence: 99%

“…2006), introduction of a tertiary amine in the ICI 182,780 side chain was associated with improved efficacy of compounds ZK-703 and ZK-253 at preventing growth of mouse xenografts from estrogen-sensitive and tamoxifen-resistant breast cancer lines (Hoffmann et al . 2004).…”

Section: Molecular Determinants Of Antiestrogenicitymentioning

confidence: 99%

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Traboulsi

Ezzy

Gleason

et al. 2017

Journal of Molecular Endocrinology

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“…Two new pure oestrogen antagonists, ZK-703 and ZK-253, which destabilise the ER, have been investigated using the MCF-7 xenograft model. ZK-703 and ZK-253 were not only more effective than either tamoxifen or fulvestrant at inhibiting the growth of ER-positive xenografts, they also showed a highly potent activity in tamoxifen-resistant xenografts (Hoffmann et al 2004). Clinical studies with both of these agents are awaited with interest.…”

Section: Other Pure Oestrogen Antagonists In Developmentmentioning

confidence: 99%

Pure oestrogen antagonists for the treatment of advanced breast cancer

Howell¹

2006

Endocr Relat Cancer

108

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For more than 30 years, tamoxifen has been the drug of choice in treating patients with oestrogen receptor (ER)-positive breast tumours. However, research has endeavoured to develop agents that match and improve the clinical efficacy of tamoxifen, but lack its partial agonist effects. The first 'pure' oestrogen antagonist was developed in 1987; from this, an even more potent derivative was developed for clinical use, known as fulvestrant (ICI 182,780, 'Faslodex'). Mechanistic studies have shown that fulvestrant possesses high ER-binding affinity and has multiple effects on ER signalling: it blocks dimerisation and nuclear localisation of the ER, reduces cellular levels of ER and blocks ER-mediated gene transcription. Unlike anti-oestrogens chemically related to tamoxifen, fulvestrant also helps circumvent resistance to tamoxifen. There are extensive data to support the lack of partial agonist effects of fulvestrant and, importantly, its lack of cross-resistance with tamoxifen. In phase III studies in patients with locally advanced or metastatic breast cancer, fulvestrant was at least as effective as anastrozole in patients with tamoxifen-resistant tumours, was effective in the first-line setting and was also well tolerated. These data are supported by experience from the compassionate use of fulvestrant in more heavily pretreated patients. Further studies are now underway to determine the best strategy for sequencing oestrogen endocrine therapies and to optimise dosing regimens of fulvestrant. At present, and for the foreseeable future, fulvestrant is the only oestrogen antagonist with no agonistic effects licensed for the treatment of advanced breast cancer in postmenopausal women. Other similar oestrogen antagonists are undergoing research and development, with a few currently being evaluated in phase II trials.

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“…The growth rates for the ZR-75-1 xenografts with 50.6 pg/ml of serum E 2 and the Br-10 xenografts with 22.9 pg/ml of serum E 2 were slow compared with the rates for MCF-7 xenografts, but, by using E 2 implants, tumor volumes were greater than 500 mm 3 after 40 days of treatment (Table I). To evaluate the antitumor activity and ER degradation of CH4893237 against human breast tumors with low serum E 2 , we first used the ZR-75-1 xenografts which have been reported to show partial tamoxifen resistance (9). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Hoffmann et al introduced an orally available steroidal SERD, ZK-253, which showed antitumor activities against ER-positive human breast cancer xenografts in 2004 (9). Dardes et al reported that an orally available nonsteroidal SERD, GW5638, was efficacious against ER-positive human breast cancer and endometrial cancer xenografts in 2002 and 2007 (10,11).…”

Section: Introductionmentioning

confidence: 99%

Effects of CH4893237, a new orally active estrogen receptor downregulator, on breast cancer xenograft models with low serum estrogen levels

Yoneya¹

2009

Oncol Rep

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Abstract. We compared the antitumor efficacy and estrogen receptor (ER) degradation of CH4893237, a new orally active selective ER downregulator, with fulvestrant and tamoxifen in human breast cancer xenografts with low levels of serum estrogen (E 2 ) (50.6, 22.9 and <16.7 pg/ml), equivalent to the ranges in postmenopausal or aromatase inhibitor-treated breast cancer patients. In addition, using proteolysis assays, we tested the conformational changes induced in ER· and ERß by CH4893237, fulvestrant, and 4-OH tamoxifen (4OHT). In ZR-75-1 xenografts with 50.6 pg/ml E 2 , CH4893237 (100 and 300 mg/kg/day p.o.) as well as fulvestrant (1 and 3 mg/body/week s.c.) showed complete growth inhibition (>90%) and tamoxifen (30 and 100 mg/kg/day p.o.) showed moderate tamoxifen resistance. The antitumor activity of CH4893237 (300 mg/kg) was the same as that of fulvestrant (3 mg/body) but the rate of ER degradation induced by CH4893237 (300 mg/kg) was significantly stronger than that of fulvestrant (3 mg/body) (94.3 vs. 85.5%, P<0.01). In Br-10 xenografts with 22.9 pg/ml E 2 , CH4893237 (30 mg/kg) and fulvestrant (1 mg/body) showed potent growth inhibition (>70%) whereas tamoxifen (1, 10 and 100 mg/kg) showed strong tamoxifen resistance. In Br-10 xenografts with ovariectomized-level E 2 (<16.7 pg/ml), tamoxifen (30 mg/kg) increased the tumor volume but CH4893237 (30 mg/kg) showed no agonistic activity. In the ER· and ERß proteolysis assays, the band pattern for CH4893237 was different from fulvestrant. Thus, CH48793237 showed potent antitumor efficacies without agonistic activity and superior ER degradation in human breast cancer xenografts with low serum E 2 . Furthermore, the proteolysis studies suggest that CH4893237 induces conformational changes of ER different from those induced by fulvestrant. Therefore, CH4893237 alone or in combination with an aromatase inhibitor may be an efficient treatment for postmenopausal breast cancer patients.

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Characterization of New Estrogen Receptor Destabilizing Compounds: Effects on Estrogen-Sensitive and Tamoxifen-Resistant Breast Cancer

Abstract: ZK-703 and ZK-253 are potent, long-term inhibitors of growth in both tamoxifen-sensitive and tamoxifen-resistant breast cancer models.

Cited by 84 publications

References 20 publications

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Pure oestrogen antagonists for the treatment of advanced breast cancer

Effects of CH4893237, a new orally active estrogen receptor downregulator, on breast cancer xenograft models with low serum estrogen levels

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