The discovery of a novel series of potential ERRα inverse agonists based on p-nitrobenzenesulfonamide template for triple-negative breast cancer in vivo

Abstract

Oestrogen related receptor α participated in the regulation of oxidative metabolism and mitochondrial biogenesis, and was overexpressed in many cancers including triple-negative breast cancer. A set of new ERRα inverse agonists based on p-nitrobenzenesulfonamide template were discovered and compound 11 with high potent activity (IC₅₀ = 0.80 μM) could significantly inhibit the transcription of ERRα-regulated target genes. By regulating the downstream signalling pathway, compound 11 could suppress the migration and invasion of the ER-negative MDA-MB-231 cell line. Furthermore, compound 11 demonstrated a significant growth suppression of breast cancer xenograft tumours in vivo (inhibition rate 23.58%). The docking results showed that compound 11 could form hydrogen bonds with Glu331 and Arg372 in addition to its hydrophobic interaction with ligand-binding domain. Our data implied that compound 11 represented a novel and effective ERRα inverse agonist, which had broad application prospects in the treatment of triple-negative breast cancer.

Keywords:

• ERRα
• TNBC
• p-Nitrobenzenesulfonamide
• inverse agonist

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China [NO. 81872744, 81973399, 81901399], the Shandong Provincial Natural Science Foundation [NO. ZR2019MH046], and Shanghai Health Commission Youth Fund Projects [20184Y0194, 20204Y0445].