2. Academic Validation
  3. Structure-activity relationship study of estrogen receptor down-regulators with a diphenylmethane skeleton

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.
Shun Nanjyo 1,  Kenji Ohgane 1,  Hiromasa Yoshioka 1,  Makoto Makishima 2,  Yuichi Hashimoto 1,  Tomomi Noguchi-Yachide 3
Affiliations

Affiliations

  • 1 Institute for Quantitative Biosciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
  • 2 Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
  • 3 Institute for Quantitative Biosciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: noguchi@iam.u-tokyo.ac.jp.
PMID: 30940565 DOI: 10.1016/j.bmc.2019.03.042
Abstract

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.

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