Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5163-7. doi: 10.1016/j.bmcl.2015.09.074. Epub 2015 Oct 3.

Abstract

Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.

Keywords: Breast cancer; Degrader; Estrogen receptor; SERD; Tamoxifen-resistant.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cinnamates / therapeutic use
  • Drug Resistance, Neoplasm
  • Estrogen Receptor Antagonists / metabolism
  • Estrogen Receptor Antagonists / therapeutic use*
  • Female
  • Indazoles / chemistry
  • Indazoles / therapeutic use*
  • Rats
  • Structure-Activity Relationship
  • Tamoxifen / therapeutic use*
  • Xenograft Model Antitumor Assays

Substances

  • 3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid
  • Antineoplastic Agents
  • Cinnamates
  • Estrogen Receptor Antagonists
  • Indazoles
  • Tamoxifen