Covalent PPARγ inverse agonism by FX-909 reveals mechanistic insights into therapeutic targeting of PPARγ/RXRα-activated urothelial carcinoma.

We investigated the conformational mechanisms underlying PPARγ activation in muscle-invasive urothelial carcinoma (MIUC) and sought to develop covalent inverse agonists to therapeutically reinforce a repressive state. The integration of mutational, structural, and biochemical analyses of PPARγ and RXRα guided the discovery of FX-909, a first-in-class clinical PPARγ inverse agonist that enforces a repressive conformational state, even in highly activated biological contexts. FX-909 is a potent, highly selective, and powerful suppressor of PPARγ transcriptional activity through the enhancement of PPARγ-nuclear co-repressor (NCOR) binding affinity. Treatment with FX-909 resulted in selective growth inhibition in PPARγ-activated MIUC cell lines and durable regressions in xenograft models of MIUC. FX-909 is capable of recapitulating PPARG genetic knockout phenotypes in vivo and is currently in clinical development for the treatment of intractable MIUC.