Wu Ke-Jia, Zhong Hai-Jing, Yang Guanjun, Wu Chun, Huang Jie-Min, Li Guodong, Ma Dik-Lung, Leung Chung-Hang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
Chem Asian J. 2018 Feb 2;13(3):275-279. doi: 10.1002/asia.201701216. Epub 2018 Jan 15.
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.
脯氨酰异构酶1（Pin1）是一种保守的酶，可调节细胞周期进程、转录调控和细胞凋亡等细胞过程。然而，Pin1的过表达与前列腺肿瘤复发的较高概率相关。我们利用分子对接技术从天然产物和类天然产物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、细胞热迁移等技术。我们通过基于结构的虚拟筛选确定化合物1为Pin1活性的类天然产物抑制剂，并表明化合物1可以靶向Pin1并破坏细胞中Pin1与NF-κB的p65亚基之间的相互作用。此外，化合物1降低了细胞核中p65（Thr254）的磷酸化并减弱了细胞中的NF-κB活性。最后，化合物1诱导前列腺癌细胞凋亡。化合物1代表一种通过靶向Pin1-NF-κB相互作用发挥作用的类天然产物Pin1抑制剂。
