Discovery of a first-in-class PROTAC degrader of RORγ for the treatment of CRPC

ROR γ has emerged as a promising therapeutic target for cancer treatment due to its pivotal role in regulating oncogenic signaling pathways, including prostate cancer. PROTAC technology is a promising therapeutic modality that degrades oncogenic proteins by hijacking the ubiquitin–proteasome system. Currently, targeting ROR γ for the treatment of prostate cancer mainly focuses on the development of small molecule inverse agonists. However, ROR γ inverse agonists have made limited clinical progress. Here, we report the discovery of a first-in-class ROR γ PROTAC degrader 3a ( XYD201 ) (DC 50 = 5.26 nmol/L, D max = 97%) derived from a ROR γ agonist. Notably, 3a significantly induced ROR γ protein degradation in a time-, dose-, and UPS-dependent manner and had potent antiproliferative activity in the CRPC cell line 22Rv1 (IC 50 = 4 nmol/L). Mechanistically, 3a inhibited the AR-related signaling pathways and suppressed key anti-apoptotic regulators in 22Rv1 cells. Importantly, 3a showed remarkable antitumor activity in the 22Rv1 xenograft tumor model in mice. Altogether, our data suggest that 3a is a promising candidate for the treatment of CRPC.