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

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Peroxisome-proliferator-activated receptor-γ (PPARγ) is a nuclear receptor and a potential therapeutic target in cancer.
• PPARγ is a critical lineage driver in muscle-invasive luminal bladder cancer.

Purpose of the Study:

• To discover novel covalent inverse-agonists of PPARγ.
• To investigate the potential of these compounds as cancer therapeutics, particularly for bladder cancer.
• To explore their interaction with corepressors NCOR1 and NCOR2.

Main Methods:

• Synthesis of chloro-nitro-arene covalent inverse-agonists featuring a benzoxazole core.
• In vitro treatment of sensitive cell lines to assess gene regulation and antiproliferative effects.
• In vivo studies to evaluate pharmacodynamic target regulation.

Main Results:

• Compounds demonstrated robust regulation of PPARγ target genes and antiproliferative effects in vitro.
• BAY-4931 and BAY-0069 showed improved in vitro potency and efficacy compared to previous inverse-agonists.
• Modest pharmacodynamic target regulation was observed in vivo despite imperfect physicochemical properties.

Conclusions:

• Novel benzoxazole-based covalent inverse-agonists of PPARγ were discovered.
• These compounds represent promising tools for investigating PPARγ inverse-agonism in vitro.
• The findings support PPARγ as a therapeutic target in bladder cancer.