9O9N

Crystal structure of PPARgamma ligand binding domain (LBD) in complex with NCoR1 corepressor peptide and inverse agonist FX-909

This is a non-PDB format compatible entry.

Summary for 9O9N

• Entry DOI: 10.2210/pdb9o9n/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, Nuclear receptor corepressor 1, (3P)-3-(5,7-difluoro-4-oxo-1,4-dihydroquinolin-2-yl)-4-(methanesulfonyl)benzonitrile, ... (4 entities in total)
• Functional Keywords: nuclear, receptor, inverse agonist, cancer, fx-909, ppar, pparg, ncor, corepressor, nuclear protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 34375.73

Authors

Laughlin, Z.T.,Dong, J.,Harp, J.M.,Kojetin, D.J. (deposition date: 2025-04-18, release date: 2025-05-14, Last modification date: 2025-09-10)

Primary citation

Laughlin, Z.T.,Arifova, L.,Munoz-Tello, P.,Yu, X.,Giridhar, M.N.K.,Dong, J.,Harp, J.M.,Zhu, D.,Kamenecka, T.M.,Kojetin, D.J.
Structural Basis of PPAR gamma-Mediated Transcriptional Repression by the Covalent Inverse Agonist FX-909.
J.Med.Chem., 68:17587-17597, 2025

PubMed Abstract: 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.

PubMed: 40797371
DOI: 10.1021/acs.jmedchem.5c01252

Experimental method

X-RAY DIFFRACTION (2.1 Å)