Structural basis of PPARγ-mediated transcriptional repression by the covalent inverse agonist FX-909.

Hyperactivation of peroxisome proliferator-activated receptor gamma (PPARγ)-mediated transcription promotes tumor growth in urothelial (bladder) cancer, which can be inhibited by pharmacological compounds that repress PPARγ activity. FX-909 is a covalent PPARγ inverse agonist currently in phase 1 clinical trials for advanced solid malignancies including muscle-invasive bladder cancer. Here, we compared the mechanism of action of FX-909 to other covalent inverse agonists including T0070907, originally reported more than 20 years ago and misclassified as an antagonist, and two recently reported improved covalent inverse agonist analogs, SR33068 and BAY-4931. Functional profiling and NMR studies reveal that FX-909 displays improved corepressor-selective inverse agonism and better stabilizes a transcriptionally repressive PPARγ LBD conformation compared to T0070907. The crystal structure of PPARγ LBD cobound to FX-909 and NCoR1 corepressor peptide reveals a repressive conformation shared by other covalent inverse agonists. These findings build on recent studies highlighting the pharmacological significance and clinical relevance of transcriptionally repressive PPARγ inverse agonists.