Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors

5 years ago

Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors

Jia Jin, Yi-qian Xie, Fei Ye, Fu-lin Lian, Hao Jiang, Yu-xi Jiang, Zhong-jie Liang, Wen-chao Lu, Wei-yao Zhang, Cheng Luo, Da-jin Wang, Zheng-bing Lv

Protein arginine methylation, a post-translational modification critical for a variety of biological processes, is catalyzed by protein arginine N-methyltransferases (PRMTs). In particular, PRMT1 is responsible for over 85% of the arginine methylation in mammalian cells. Dysregulation of PRMT1 is involved in diverse pathological diseases including cancers. However, most current PRMT1 inhibitors are lack of specificity, efficacy, and bioavailability. Herein, a series of alkyl bis(oxy)dibenzimidamide derivatives were identified as selective PRMT1 inhibitors. Among them, the most potent compound corresponds to hexamidine (IC50 = 5.9 ± 1.7 μm), which is an antimicrobial agent. The binding between hexamidine and PRMT1 was further validated by thermal shift assays and nuclear magnetic resonance (NMR) experiments. Molecular docking and NMR assays indicated that hexamidine occupied the substrate binding pocket. Furthermore, hexamidine effectively blocked cell proliferation in cancer cell lines related to PRMT1 overexpression. Taken together, this study has provided a druggable scaffold targeting PRMT1 as well as a new way to repurpose old drugs which is a complementary tool for the discovery of new lead compounds. By combining a shape-based scaffold hopping approach, TR-FRET and radioactive methylation assays, we have identified a series of alkyl bis(oxy)dibenzimidamide derivatives as selective PRMT1 inhibitors. Among them, the most potent compound corresponds to hexamidine, which is an antimicrobial agent, displayed previously unreported inhibitory activity against PRMT1 (IC50 = 5.9 ± 1.7 μm). Molecular docking and NMR assays indicated that hexamidine occupied the substrate binding pocket.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13047