Inverse Agonists of Peroxisome Proliferator-Activated Receptor Gamma: Advances and Prospects in Cancer Treatment

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear transcription factor that modulates metabolic homeostasis and cell proliferation. Inverse agonism of PPARγ is an emerging anticancer strategy, particularly for the treatment of bladder cancer. The first-in-class PPARγ inverse agonist, FX-909, is currently being studied in clinical trials for cancer treatment. However, PPARγ inverse agonists are still in the early stages of development. The discovery of compounds with novel chemical structures, potent efficacy, and favorable pharmacokinetic properties is urgently needed. In this perspective, the biological functions of PPARγ and its role in cancer pathology are introduced, and currently available PPARγ inverse agonists and their preliminary structure–activity relationships (SARs) are discussed from a medicinal chemistry viewpoint. These findings inform the development of anticancer agents that act as PPARγ inverse agonists. Furthermore, our discussion of the complex biological functions of PPARγ provides insights into the exploration of its role in various diseases.