One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors

• Published in: European journal of medicinal chemistry Vol. 281; pp. 116970 - 116987
• Main Authors: Li, Huaxuan, Yang, Hong, Liu, Li, Zheng, Jiahong, Shi, Qiongyu, Li, Bang, Wang, Xingcan, Zhang, Ying, Zhou, Ruilin, Zhang, Jian, Chen, Zhong-Zhu, Wang, Chang-Yun, Wang, Yuanxiang, Huang, Xun, Liu, Zhiqing
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.01.2025; Elsevier
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Arginine - analogs & derivatives; Arginine - chemistry; Arginine - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Life Sciences & Biomedicine; Metabolic stability; Mice; Mice, Nude; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Nucleoside derivatives; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Pharmacology & Pharmacy; Piperazine; Piperazine - chemical synthesis; Piperazine - chemistry; Piperazine - pharmacology; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Protein arginine methyltransferase 5; Protein-Arginine N-Methyltransferases - antagonists & inhibitors; Protein-Arginine N-Methyltransferases - metabolism; Science & Technology; Structure-Activity Relationship; Symmetric dimethylarginines; MMA; PRMT5; Nucleoside derivatives; 9-BBN; DNMT1; SAR; Protein arginine methyltransferase 5; DIPEA; PRMTs; Pd(dppf)Cl2; sDMA; Metabolic stability; MTAP; Piperazine; TGI; PI; MTA; Symmetric dimethylarginines; SAM; METHYLATION; JNJ-64619178; DISCOVERY; ARGININE METHYLTRANSFERASE 5; DELETION
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116970

The protein arginine methyltransferase 5 (PRMT5) has emerged as potential target for the treatment of cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors targeting either S-adenosyl methionine (SAM) pocket or substrate binding pocket. Here, we rationally designed a series of nucleoside derivatives incorporated with piperazine as novel PRMT5 inhibitors occupying both pockets. The representative compound 36 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other methyltransferases. Further cellular experiments revealed that compound 36 potently reduced the level of symmetric dimethylarginines (sDMA) and inhibited the proliferation of MOLM-13 cell lines by inducing apoptosis and cell cycle arrest. Moreover, compound 36 had more favorable metabolic stability and aqueous solubility than JNJ64619178 (9). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that 36 is a highly potent and selective PRMT5 inhibitor worthy for further development. [Display omitted] •New PRMT5 inhibitors incorporated with piperazine were discovered.•Compound 36 displayed improved aqueous solubility and metabolic stability than 9.•Compound 36 occupys both SAM pocket and substrate binding pocket simultaneously.