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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Prostate cancer (PC) is a leading global cancer in men.
• Androgen deprivation therapy (ADT) resistance leads to castration-resistant prostate cancer (CRPC).
• The protein arginine methyltransferase 5 (PRMT5) and pICLn interaction promotes DNA double-strand break (DSB) repair gene transcription, contributing to therapy resistance.

Purpose of the Study:

• To identify and evaluate compounds that disrupt the PRMT5/pICLn interaction.
• To assess the efficacy of a novel compound, J021-0199, in inhibiting CRPC cell growth and overcoming therapy resistance.

Main Methods:

• High-throughput screening identified J021-0199 as a PRMT5/pICLn interaction inhibitor.
• Biochemical assays confirmed J021-0199 binding to the PRMT5 N-terminal TIM barrel domain.
• In vitro studies in CRPC cell lines (LNCaP, 22Rv1) assessed cell growth inhibition and DNA damage response (DDR) gene expression via qPCR.

Main Results:

• J021-0199 selectively inhibited growth in CRPC cell lines.
• The compound demonstrated binding to the PRMT5 protein.
• J021-0199 treatment led to the downregulation of key DDR genes involved in homologous recombination, nonhomologous end joining, and G2 arrest.

Conclusions:

• J021-0199 effectively disrupts the PRMT5/pICLn interaction, a key driver of therapy resistance in CRPC.
• The compound shows significant potential as a lead molecule for developing new therapies against CRPC.
• Targeting the PRMT5/pICLn pathway offers a promising strategy to overcome treatment resistance in prostate cancer.