Shen Zhihang, Seabra Gustavo, Li Chenglong
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
ACS Med Chem Lett. 2025 Apr 25;16(5):875-879. doi: 10.1021/acsmedchemlett.5c00126. eCollection 2025 May 8.
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.
前列腺癌（PC）是全球男性中最常被诊断出的癌症。虽然雄激素剥夺疗法（ADT）最初是有效的，但许多患者会产生耐药性，进而发展为去势抵抗性前列腺癌（CRPC）。最近的研究已经确定PRMT5（蛋白质精氨酸甲基转移酶5）和pICLn之间的相互作用是一个有前景的治疗靶点，因为它促进了有助于治疗耐药性的双链断裂（DSB）修复基因的转录。为了靶向这条通路，一项筛选活动确定J021-0199是一种潜在的命中化合物，它能破坏PRMT5/pICLn的相互作用。生化分析表明J021-0199与PRMT5的N端TIM桶状结构域结合。在CRPC细胞系（LNCaP和22Rv1）中，J021-0199选择性地抑制癌细胞生长。qPCR分析进一步揭示了参与同源重组、非同源末端连接和G2期阻滞的DNA损伤反应（DDR）基因的下调。这些结果支持J021-0199作为一种有前景的先导化合物，用于克服CRPC中的耐药性。
