Discovery and Structure-Based Design of Potent Covalent PPAR gamma Inverse-Agonists BAY-4931 and BAY-0069

The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-gamma (PPARG or PPAR gamma) represents a potential target for a new generation of cancer therapeutics, especially in muscle-invasive luminal bladder cancer where PPAR gamma is a critical lineage driver. Here we disclose the discovery of a series of chloro-nitro-arene covalent inverse-agonists of PPAR gamma that exploit a benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2. In vitro treatment of sensitive cell lines with these compounds results in the robust regulation of PPAR gamma target genes and antiproliferative effects. Despite their imperfect physicochemical properties, the compounds showed modest pharmacodynamic target regulation in vivo. Improvements to the in vitro potency and efficacy of BAY-4931 and BAY-0069 compared to those of previously described PPAR gamma inverse-agonists show that these compounds are novel tools for probing the in vitro biology of PPAR gamma inverse-agonism.

Automated summary

This study reveals a series of covalent inverse-agonists of PPAR gamma that interact with corepressors NCOR1 and NCOR2, resulting in regulation of PPAR gamma target genes and antiproliferative effects in sensitive cell lines. Despite their imperfect physicochemical properties, these compounds show modest pharmacodynamic target regulation in vivo, making them novel tools for probing the biology of PPAR gamma inverse-agonism in vitro.