Discovery of novel indole derivatives as LRH-1 antagonists for the treatment of castration resistant prostate cancer.

Liver receptor homolog-1 (LRH-1) is a key regulator in multiple cancers, including prostate cancer, making its antagonists a promising therapeutic strategy. However, the development of potent LRH-1 antagonists remains largely inadequate, underscoring an urgent unmet need for novel candidates with therapeutic potential. Herein, we report the discovery and characterization of a novel class of indole-based LRH-1 antagonists. Starting from high-throughput virtual screening, we employed structure-based drug design strategy to optimize lead compounds, yielding 26 (XY25026) and 28 (XY25028), which exhibit potent LRH-1inhibition with IC50 values of 280 nM and 300 nM, respectively. In cellular assays, 26 and 28 inhibited the cell proliferation across a panel of androgen receptor (AR)-positive prostate cancer cell lines with distinct androgen responsiveness and AR signaling profiles and suppressed AR target genes (KLK2 and KLK3). Importantly, oral administration of 26 and 28 elicited significant in vivo antitumor efficacy in a 22Rv1 xenograft model, with no detectable systemic toxicity observed in treated mice. These results identify 26 and 28 as promising orally bioavailable LRH-1 antagonists, validating them as attractive lead molecules for further structural optimization and development for castration-resistant prostate cancer (CRPC) therapy.