Design, synthesis and evaluation of antitumor activity of selective PRMT6 inhibitors

• Published in: European journal of medicinal chemistry Vol. 247; pp. 115032 - 115046
• Main Authors: Zhang, Qiangsheng, Cao, Jiaying, Zhang, Yiqian, Bi, Zhenfei, Feng, Qiang, Yu, Luoting, Li, Lu
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.02.2023; Elsevier
• Subjects: Anticancer agents; Chemistry, Medicinal; Histone methylation; Humans; Life Sciences & Biomedicine; Methylation; Neoplasms; Nuclear Proteins - metabolism; Pharmacology & Pharmacy; PRMT6; Protein-Arginine N-Methyltransferases; Repressor Proteins - metabolism; Science & Technology; Selectivity; PRMT6; Selectivity; Anticancer agents; Histone methylation; METHYLTRANSFERASE PRMT6; ARGININE METHYLATION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.115032

PRMT6 is a member of the protein arginine methyltransferase family, which is involved in a variety of physiological processes and plays an important role in the occurrence and development of tumors. Due to the high homology of type Ⅰ PRMTs and the two close binding sites of the SAM pocket and the substrate pocket, selective PRMT6 inhibitors have rarely been reported. In this study, a series of (5-phenylpyridin-3-yl)methanamine derivatives were designed and synthesized, which could form hydrogen bonding interactions with the unique Glu49 of PRMT6, thereby improving the selectivity of the compounds for PRMT6. Among them, a25 had the best activity and selectivity, with more than 25-fold selectivity for PRMT1/8 and more than 50-fold selectivity for PRMT3/4/5/7, which was superior to these reported SAM competitive and substrate competitive PRMT6 inhibitors. Importantly, a25 could significantly inhibit the proliferation of various tumor cells and effectively induce apoptosis of cancer cells. Our data clarified that a25 is a promising selective PRMT6 inhibitor for cancer therapy which is worthy of further evaluation. [Display omitted] •A series of novel and selective PRMT6 inhibitors have been synthesized.•a25 was 30-fold selective for PRMT1 and 28-fold selective for PRMT8.•a25 significantly inhibit the proliferation of various tumor cells.•a25 showed reasonable pharmacokinetic profile.