Virtual High-Throughput Screening of Ligands for Disrupting PRMT5/pICLn Interaction in Prostate Cancer Cells

Prostate cancer (PC) is the most commonly diagnosed cancer in men worldwide. While androgen deprivation therapy (ADT) is initially effective, many patients develop resistance, progressing to castration-resistant prostate cancer (CRPC). Recent studies have identified the interaction between PRMT5 (protein arginine methyltransferase 5) and pICLn as a promising therapeutic target, as it promotes the transcription of double-strand break (DSB) repair genes that contribute to therapy resistance. To target this pathway, a screening campaign identified J021-0199 as a potential hit compound that disrupts the PRMT5/pICLn interaction. Biochemical assays demonstrated that J021-0199 binds to the N-terminal TIM barrel domain of PRMT5. In CRPC cell lines (LNCaP and 22Rv1), J021-0199 selectively inhibited cancer cell growth. qPCR analysis further revealed downregulation of DNA damage response (DDR) genes involved in homologous recombination, nonhomologous end joining, and G2 arrest. These results support J021-0199 as a promising lead compound for overcoming resistance in CRPC.