The discovery of novel, potent ERR-alpha inverse agonists for the treatment of triple negative breast cancer

European Journal of Medicinal Chemistry
Yongli DuQunyi Li

Abstract

The estrogen-related receptor α (ERRα) is an orphan receptor and a novel target for solid tumor therapy, conceivably through effects on the regulation of tumor cell energy metabolism associated with energy stress within solid tumor micro environments. Here we describe the discovery of novel potent inverse agonists of ERRα. In vitro, compound 11 potently inhibits ERRα's transcriptional activity by preventing endogenous PGC-1α and ERRα binding and suppresses the proliferation of different human cancer cell lines and the migration of breast cancer cells (MDA-MB-231). In vivo, compound 11 demonstrates a strong inhibitory effect on the growth of human breast cancer xenografts (MDA-MB-231) and the tumor growth is inhibited by 40.9% after treating with compound 11 (30 mg/kg). The binding mode shows that compound 11 interacts with the binding pocket of ERRα through hydrogen interactions with the residue Gly397 and hydrophobic interactions with the hydrophobic residues. All these results suggest that compound 11 represents a novel potent ERRα inverse agonist and is promising in the discovery of antitumor compounds for the treatment of triple negative breast cancer.

Citations

Sep 5, 2020·Molecular Diversity·Nitish KumarPreet Mohinder Singh Bedi
Aug 21, 2020·Pharmaceutical Patent Analyst·Hermann Am Mucke
Oct 30, 2020·Cells·Oliver TreeckOlaf Ortmann
May 1, 2021·International Journal of Molecular Sciences·Zhipei GaoJingkang Shen
Jun 1, 2021·ACS Medicinal Chemistry Letters·Tsuyoshi ShinozukaKenji Wakabayashi
Jun 6, 2021·Journal of Cancer Research and Clinical Oncology·Susanne Schüler-ToprakOliver Treeck
Nov 7, 2021·The Journal of Pharmacology and Experimental Therapeutics·Tianxiao WangQunyi Li

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