2. Academic Validation
  3. Design, synthesis and evaluation of antitumor activity of selective PRMT6 inhibitors

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

  • Eur J Med Chem. 2023 Feb 5;247:115032. doi: 10.1016/j.ejmech.2022.115032.
Qiangsheng Zhang 1,  Jiaying Cao 1,  Yiqian Zhang 1,  Zhenfei Bi 1,  Qiang Feng 2,  Luoting Yu 1,  Lu Li 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu, 610041, PR China.
  • 2 College of Chemistry and Life Science, Chengdu Normal University, Chengdu, 611130, PR China.
  • 3 NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Laboratory of Clinical Pharmacology, GCP Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, PR China. Electronic address: [email protected].
PMID: 36566712 DOI: 10.1016/j.ejmech.2022.115032
Abstract

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.

Keywords

Anticancer agents; Histone methylation; PRMT6; Selectivity.

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