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Updated: Apr 12, 2026
Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
Published on: December 19, 2018
Synthesis and evaluation of tamoxifen derivatives with a long alkyl side chain as selective estrogen receptor
Takuji Shoda1, Masashi Kato2, Rintaro Harada1
1Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Abstract:
Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. An antagonist that acts as not only an inhibitor of ligand binding but also an inducer of the down-regulation of ER would be useful for the treatment for ER-positive breast cancer. We previously reported the design and synthesis of a selective estrogen receptor down-regulator (SERD), (E/Z)-4-(1-{4-[2-(dodecylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl)phenol (C12), which is a tamoxifen derivative having a long alkyl chain on the amine moiety. This compound induced degradation of ERα via a proteasome-dependent pathway and showed an antagonistic effect in MCF-7 cells. With the aim of increasing the potency of SERDs, we designed and synthesized various tamoxifen derivatives that have various lengths and terminal groups of the long alkyl side chain. During the course of our investigation, C10F having a 10-fluorodecyl group on the amine moiety of 4-OHT was shown to be the most potent compound among the tamoxifen derivatives. Moreover, computational docking analysis suggested that the long alkyl chain interacted with the hydrophobic region on the surface of the ER, which is a binding site of helix 12 and coactivator. These results provide useful information to develop promising candidates as SERDs.
Insights
Researchers developed novel tamoxifen derivatives as selective estrogen receptor down-regulators (SERDs) for breast cancer treatment. The most potent compound, C10F, effectively degrades estrogen receptors (ERs) and shows promise for ER-positive breast cancer therapy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Estrogen receptors (ERs) are crucial for ER-positive breast cancer growth.
- Selective estrogen receptor down-regulators (SERDs) that inhibit ligand binding and induce ER degradation are needed for treatment.
Purpose of the Study:
- To design and synthesize novel tamoxifen derivatives with enhanced potency as SERDs.
- To investigate the structure-activity relationship of alkyl chain modifications on tamoxifen derivatives.
- To evaluate the efficacy of these compounds in degrading ERα and exhibiting antagonistic effects.
Main Methods:
- Synthesis of various tamoxifen derivatives with modified alkyl side chains.
- Evaluation of ERα degradation via proteasome-dependent pathways.
- Assessment of antagonistic effects in MCF-7 breast cancer cells.
- Computational docking analysis to understand ligand-receptor interactions.
Main Results:
- A novel tamoxifen derivative, C10F, featuring a 10-fluorodecyl group, demonstrated superior potency compared to other derivatives.
- C10F induced ERα degradation through a proteasome-dependent pathway.
- Computational analysis revealed hydrophobic interactions of the alkyl chain with ER, influencing helix 12 and coactivator binding.
Conclusions:
- The study identified C10F as a highly potent SERD candidate.
- Structural modifications, particularly the alkyl chain, are critical for SERD efficacy.
- These findings offer valuable insights for developing advanced SERDs for ER-positive breast cancer treatment.
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