GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE298nnn/GSE298628/primaryOK200GenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE298628GEOGSEfalseGenome-wide occupancy of PPARG and RXRA after treatment with PPARG inverse agonistWe report our mechanistic investigation into the conformationally-driven activation bias of PPARG in muscle-invasive urothelial cancer (MIUC) and our efforts to pharmacologically reverse this activation bias through covalent PPARG inverse agonism. Studies into tumor-associated mutations in both PPARG and RXRA were integrated with structure-based drug design as well as insights from biochemical mechanistic studies to discover FX-909, a first-in-class clinical PPARG inverse agonist that robustly enforces a conformationally repressive state of PPARG, even in highly activated biological contexts. FX-909 is a potent, highly selective, and powerful suppressor of PPARG transcriptional activity through enhancement of PPARG-NCOR (Nuclear Co-Repressor) binding affinity. Treatment with FX-909 resulted in selective growth inhibition in PPARG-activated MIUC cell lines. Further, FX-909 achieved durable regressions in xenograft models of MIUC. FX-909 is the first chemical tool that is capable of recapitulating PPARG genetic knockout in vivo and is currently in clinical development for the treatment of intractable MIUC.2026/05/28GSE298628GSM9019641GSM9019640GSM9019643GSM9019642GSM9019645GSM9019644GSM9019647GSM9019646GSM9019649GSM901964820795298628Homo sapiens