An orally available inverse agonist of estrogen-related receptor gamma showed expanded efficacy for the radioiodine therapy of poorly differentiated thyroid cancer

Eur J Med Chem. 2020 Nov 1:205:112501. doi: 10.1016/j.ejmech.2020.112501. Epub 2020 Jul 14.

Abstract

Estrogen-related receptor gamma (ERRγ) is the NR3B subgroup of associated transcription factors. In this report, a new generation of a potent and selective ERRγ inverse agonist (25) with good biocompatibility was proposed. We also explored the potential of the newly developed compound 25 in the PDTC model to expand the original indications from ATC. In addition, an X-ray crystallographic study of the ligand and ERRγ co-complex showed that 25 completely binds to the target protein (PDB 6KNR). Its medicinal chemistry, including a distinctive structural study to in vivo results, denotes that 25 may be directed towards the development of a pivotal treatment for ERRγ-related cancers.

Keywords: ADMET; ATC; ERRγ inverse agonist; NIS; PDTC; X-ray crystallography.

MeSH terms

  • Administration, Oral
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Biological Availability
  • Cell Line, Tumor
  • Drug Inverse Agonism*
  • Humans
  • Iodine Radioisotopes / therapeutic use*
  • Molecular Docking Simulation
  • Protein Conformation
  • Receptors, Estrogen / antagonists & inhibitors*
  • Receptors, Estrogen / chemistry
  • Receptors, Estrogen / metabolism
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / radiotherapy

Substances

  • Antineoplastic Agents
  • ESRRG protein, human
  • Iodine Radioisotopes
  • Receptors, Estrogen