Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers

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. We utilized studies into tumor-associated mutations in both PPARG and RXRA, as well as a combination of structure-based drug design merged with 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 contexts such as RXRA S427F mutation and PPARG amplification. FX-909 is a potent, highly selective, and powerful suppressor of PPARG transcriptional activity through enhancement of PPARG nuclear corepressor binding (NCOR) 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 through inverse agonism of PPARG. FX-909 is the first chemical tool available to the community that is capable of recapitulating PPARG genetic knockout in vivo and is currently in clinical development for the treatment of intractable MIUC. Competing Interest Statement Authors are shareholders in Flare Therapeutics.