Diao TongXiang, Feng Chen, Liu Shuai, Song Jia-Li, Zhu Kong-Kai, Jiang Cheng-Shi, Fu Qiang
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Engineering Laboratory of Urinary Organ and Functional Reconstruction of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Chem Biol Drug Des. 2025 Jun;105(6):e70136. doi: 10.1111/cbdd.70136.
Protein arginine methyltransferase 5 (PRMT5) is an epigenetic-related enzyme that has been shown to be a promising target for the treatment of human cancers. In prostate cancer, gene knockout has been shown to inhibit cancer cells by regulating the androgen receptor (AR), but this method has no effect on advanced prostate cancer without AR expression, and existing anticancer drugs are effective only in the current stage and promote the progression of cancer to advanced prostate cancer. We hope to design and synthesize a new compound that can inhibit prostate cancer at different stages. A series of candidate PRMT5 inhibitor molecules were designed on the basis of virtual molecular docking screening, and the binding mode was predicted via molecular docking simulation. Prostate cancer cell proliferation was detected by CCK-8, EdU, and flow assays, which verified the changes in the cancer cell cycle. Migration and invasion assays verified the effects of the compounds on the metastatic function of prostate cancer cells. Finally, Western blotting was used to detect the mechanism of action of the compounds in the treatment of prostate cancer. In prostate cancer, gene knockout has been shown to inhibit cancer cells by regulating the AR, but it has no effect on advanced prostate cancer without AR expression, and existing anticancer drugs are effective only in the current stage and promote the progression of cancer to advanced prostate cancer. SJL2-1 may be a promising compound for novel therapies for early androgen-sensitive prostate cancer and advanced castration-resistant prostate cancer (CRPC).
蛋白质精氨酸甲基转移酶5（PRMT5）是一种与表观遗传学相关的酶，已被证明是治疗人类癌症的一个有前景的靶点。在前列腺癌中，基因敲除已被证明可通过调节雄激素受体（AR）来抑制癌细胞，但这种方法对无AR表达的晚期前列腺癌无效，且现有的抗癌药物仅在当前阶段有效，并会促进癌症发展为晚期前列腺癌。我们希望设计并合成一种能在不同阶段抑制前列腺癌的新化合物。基于虚拟分子对接筛选设计了一系列PRMT5抑制剂候选分子，并通过分子对接模拟预测了其结合模式。通过CCK-8、EdU和流式细胞术检测前列腺癌细胞增殖，验证癌细胞周期的变化。迁移和侵袭实验验证了这些化合物对前列腺癌细胞转移功能的影响。最后，采用蛋白质免疫印迹法检测这些化合物治疗前列腺癌的作用机制。在前列腺癌中，基因敲除已被证明可通过调节AR来抑制癌细胞，但对无AR表达的晚期前列腺癌无效，且现有的抗癌药物仅在当前阶段有效，并会促进癌症发展为晚期前列腺癌。SJL2-1可能是用于早期雄激素敏感性前列腺癌和晚期去势抵抗性前列腺癌（CRPC）新疗法的一种有前景的化合物。
