Prolyl‐isomerase 1 (Pin1) is a conserved enzyme that regulates cell processes such as cell cycle progression, transcriptional regulation, and apoptosis. However, overexpression of Pin1 is correlated with a higher probability of prostate tumor recurrence. We utilized a molecular docking technique to identify Pin1 inhibitors from a database of natural product and natural product‐like compounds. The action of the hit compounds against Pin1 activity was studied using multiple methods, including a fluorometric enzymatic assay, co‐immunoprecipitation, western blotting, cell thermal shiftm, and other techniques. We have identified compound 1 as a natural‐product‐like inhibitor of Pin1 activity via structure‐based virtual screening and showed that compound 1 could target Pin1 and disrupt the interaction between Pin1 and the p65 subunit of NF‐κB in cells. Furthermore, compound 1 reduced nuclear p65 (Thr254) phosphorylation and attenuated NF‐κB activity in cells. Finally, compound 1 induced apoptosis in prostate cancer cells. Compound 1 represents a natural product‐like Pin1 inhibitor that acts via targeting the Pin1–NF‐κB interaction.

中文翻译：

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小分子Pin1抑制剂阻断前列腺癌细胞中的NF-κB信号传导。

脯氨酰异构酶1（Pin1）是一种保守的酶，可调节细胞过程，例如细胞周期进程，转录调节和细胞凋亡。但是，Pin1的过表达与前列腺肿瘤复发的可能性更高有关。我们利用分子对接技术从天然产物和类似天然产物的化合物数据库中鉴定Pin1抑制剂。使用多种方法研究了命中化合物对Pin1活性的作用，包括荧光酶法，免疫共沉淀，蛋白质印迹，细胞热转移和其他技术。通过基于结构的虚拟筛选，我们已经确定化合物 1是Pin1活性的天然产物样抑制剂，并显示化合物 1可能靶向于Pin1并破坏Pin1与细胞中NF-κB的p65亚基之间的相互作用。此外，化合物 1减少细胞中的核p65（Thr254）磷酸化并减弱NF-κB活性。最后，化合物 1诱导前列腺癌细胞的凋亡。化合物 1代表天然的类Pin1抑制剂，可通过靶向Pin1-NF-κB相互作用来发挥作用。