Cell chemical biology · 2026
Covalent PPARγ inverse agonism by FX-909 reveals mechanistic insights into therapeutic targeting of PPARγ/RXRα-activated urothelial carcinoma.
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Stuckey Jacob I, Mertz Jennifer A, Wilson Jonathan E, Williamson Kaylyn E, Li Yong, Kuljanin Miljan, Setser Jeremy W, DeLaBarre Byron, Chenail Gregg, Nguyen Phuong A, Scott Mark E, Geier Michael J, Bailey Christopher M, Motley William W, Audia James E, Sims Robert J
Аннотация
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.