A New Era for PPARγ: Covalent Ligands and Therapeutic Applications

Peroxisome proliferator-activated receptor γ (PPARγ) is a prominent ligand-inducible transcription factor involved in adipocyte differentiation, glucose homeostasis, insulin sensitivity, inflammation, and cell proliferation, making it a therapeutic target for diabetes, metabolic syndrome, autoimmune diseases, and cancer. Historically, drug discovery efforts focused on reversible full agonists of PPARγ for metabolic disorders; however, full receptor activation is associated with undesirable side effects. In the past decade, there has been a resurgence in research activity, primarily directed at strategies to partially activate or repress this target. In particular, many small covalent PPARγ ligands with various functionalities and therapeutic potential for several indications have been identified. Herein, we summarize the state of play in the PPARγ covalent modulator field. Critical chemical and structural biology related considerations relevant to covalent modulation of PPARγ are emphasized, with a focus on key insights that have enabled the first drug candidates to progress into the clinic.