Molecular Glue cc-885 Inhibits VHL-Deficient Clear Cell Renal Cell Carcinoma via ETS1 Degradation

Clear cell renal cell carcinoma (ccRCC) is a common and aggressive form of kidney cancer with VHL mutations present in > 50% of cases. These mutations lead to dysregulation of hypoxia-inducible factors (HIFs) and activation of oncogenic pathways, making VHL-deficient ccRCC a challenging target for therapy. In this study, we identified cc-885, a molecular glue degrader, as a selective inhibitor of VHL-deficient ccRCC. cc-885 promotes ubiquitination and degradation of transcription factor ETS1, which cooperates with EPAS1 (HIF-2α) to drive tumorigenesis. We demonstrated that cc-885 selectively targeted the p51 and p42 isoforms of ETS1, disrupting p27/p51 balance and suppressing ETS1 transcriptional activity. Moreover, combining cc-885 with an EPAS1 inhibitor, belzutifan, significantly enhanced the anti-tumor efficacy. Our findings provide a novel and precise therapeutic strategy for VHL-deficient ccRCC by targeting ETS1 degradation and disrupting the ETS1-EPAS1 complex.