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Updated: Sep 11, 2025

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Structural Basis of PPARγ-Mediated Transcriptional Repression by the Covalent Inverse Agonist FX-909
Zane T Laughlin1, Liudmyla Arifova1,2, Paola Munoz-Tello1
1Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
None:
Hyperactivation of peroxisome proliferator-activated receptor γ-mediated transcription promotes tumor growth in urothelial (bladder) cancer, which can be inhibited by compounds that repress PPARγ activity. FX-909 is a covalent PPARγ inverse agonist 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, reported more than 20 years ago and misclassified as an antagonist, and two 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 the 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.
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