2. Academic Validation
  3. Development of bivalent triarylalkene- and cyclofenil-derived dual estrogen receptor antagonists and downregulators

Development of bivalent triarylalkene- and cyclofenil-derived dual estrogen receptor antagonists and downregulators

  • Eur J Med Chem. 2020 Apr 15:192:112191. doi: 10.1016/j.ejmech.2020.112191.
Alexandra Knox 1,  Christina Kalchschmid 1,  Daniela Schuster 2,  Francesca Gaggia 1,  Claudia Manzl 3,  Daniel Baecker 1,  Ronald Gust 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innsbruck, Austria.
  • 2 Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innsbruck, Austria; Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University, Salzburg, Austria.
  • 3 Institute for Pathology, Neuropathology and Molecular Pathology, Medical University Innsbruck, Innsbruck, Austria.
  • 4 Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innsbruck, Austria. Electronic address: ronald.gust@uibk.ac.at.
PMID: 32169784 DOI: 10.1016/j.ejmech.2020.112191
Abstract

Up to 80% of mammary carcinoma initially exhibit estrogen-dependent growth, which can be treated by aromatase inhibitors or SERMs/SERDs. To increase the options after failure of the hormonal therapy with these drugs, the search for alternatives with a different mode of action to prevent estrogen action is of high relevance. Therefore, this study focused on the inhibition of coactivator recruitment at the Estrogen Receptor (ER) by targeted attachment of bivalent compounds at the coactivator binding site besides the primary binding at the ligand binding domain. Eight homodimeric 4-[1-(4-hydroxyphenyl)-2-phenyl-1-butenyl]cinnamic acid (GW7604)- or cyclofenilacrylic acid-based ER ligands with diaminoalkane linkers (C2-C5) were synthesized and their effects on the ER subtypes were assessed in vitro. All compounds possessed full antagonistic potency at ERα/β as determined in a transactivation assay. Furthermore, they exerted medium downregulatory effects dependent on the spacer length and did not stimulate the ER expression as observed for 4-hydroxytamoxifen. The cyclofenil-derived dimer with C4 spacer (15b) showed the highest binding affinity to ERα (RBA = 79.2%) and downregulated the ER content in MCF-7 cells with an efficiency of 38% at 1 μM.

Keywords

Coactivator binding site; Dual binding mode; Estrogen receptor; Homodimeric ligands; SERDs.

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