GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE298nnn/GSE298581/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE298581GEOGSEfalseGlobal gene expression response to PPARG inhibition in three urothelial cancer cell linesWe 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.2026/05/28GSE298581GSM9017839GSM9017881GSM9017880GSM9017861GSM9017883GSM9017882GSM9017860GSM9017841GSM9017885GSM9017863GSM9017884GSM9017862GSM9017840GSM9017865GSM9017843GSM9017864GSM9017842GSM9017886GSM9017867GSM9017845GSM9017844GSM9017866GSM9017847GSM9017869GSM9017868GSM9017846GSM9017849GSM9017848GSM9017870GSM9017850GSM9017872GSM9017871GSM9017874GSM9017852GSM9017873GSM9017851GSM9017876GSM9017854GSM9017875GSM9017853GSM9017878GSM9017856GSM9017855GSM9017877GSM9017858GSM9017879GSM9017857GSM901785934284298581Homo sapiens