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Global gene expression response to PPARG inhibition in three urothelial cancer cell lines

ABSTRACT: We 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298581 | GEO | 2026/05/28

REPOSITORIES: GEO

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Genome-wide occupancy of PPARG and RXRA after treatment with PPARG inverse agonist

Project description:We 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.

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