Structure-activity relationship study of estrogen receptor down-regulators with a diphenylmethane skeleton

Bioorg Med Chem. 2019 May 15;27(10):1952-1961. doi: 10.1016/j.bmc.2019.03.042. Epub 2019 Mar 26.


Selective estrogen receptor (ER) down-regulators (SERDs) are pure ER antagonists that also induce ER degradation upon binding to the receptor. Although SERDs have been developed for the treatment of ER-positive breast cancers for nearly a decade, their precise mechanism(s) of action and structure-activity relationship are still unclear. Generally, Western blotting is used to examine the effects of SERDs on ER protein levels, but the methodology is low-throughput and not quantitative. Here, we describe a quantitative, high-throughput, luciferase-based assay for the evaluation of SERDs activity. For this purpose, we established stable recombinant HEK-293 cell lines expressing ERα fused with emerald luciferase. We also designed and synthesized new diphenylmethane derivatives as candidate SERDs, and evaluated their SERDs activity using the developed system in order to examine their structure-activity relationship, taking EC50 as a measure of potency, and Emax as a measure of efficacy.

Keywords: Degradation; Down-regulation; Estrogen receptor; SERD; Structural development; Structure-activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzhydryl Compounds / chemistry*
  • Benzhydryl Compounds / pharmacology
  • Binding Sites
  • Cyclofenil / chemistry
  • Cyclofenil / metabolism
  • Down-Regulation / drug effects*
  • Estrogen Antagonists / chemistry
  • Estrogen Antagonists / metabolism
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha / antagonists & inhibitors*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation
  • Phenols / chemistry
  • Phenols / pharmacology
  • Protein Binding
  • Protein Structure, Tertiary
  • Structure-Activity Relationship


  • Benzhydryl Compounds
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Phenols
  • Cyclofenil
  • diphenylmethane
  • bisphenol A