Discovery of a first-in-class degrader for the protein arginine methyltransferase 6 (PRMT6)

Hongling Yang; Qiangsheng Zhang; Shuyan Zhou; Zuli Hu; Qing Tang; Zulong Li; Qiang Feng; Luoting Yu

doi:10.1016/j.bioorg.2024.107439

Discovery of a first-in-class degrader for the protein arginine methyltransferase 6 (PRMT6)

Bioorg Chem. 2024 May 10:148:107439. doi: 10.1016/j.bioorg.2024.107439. Online ahead of print.

Authors

Hongling Yang¹, Qiangsheng Zhang¹, Shuyan Zhou¹, Zuli Hu¹, Qing Tang², Zulong Li¹, Qiang Feng³, Luoting Yu⁴

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China.
² School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.
³ College of Chemistry and Life Science, Chengdu Normal University, Chengdu 611130, China.
⁴ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China. Electronic address: yuluot@scu.edu.cn.

PMID: 38754310
DOI: 10.1016/j.bioorg.2024.107439

Abstract

PRMT6 is a member of the protein arginine methyltransferase family, which participates in a variety of physical processes and plays an important role in the occurrence and development of tumors. Using small molecules to design and synthesize targeted protein degraders is a new strategy for drug development. Here, we report the first-in-class degrader SKLB-0124 for PRMT6 based on the hydrophobic tagging (HyT) method.Importantly, SKLB-0124 induced proteasome dependent degradation of PRMT6 and significantly inhibited the proliferation of HCC827 and MDA-MB-435 cells. Moreover, SKLB-0124 effectively induced apoptosis and cell cycle arrest in these two cell lines. Our data clarified that SKLB-0124 is a promising selective PRMT6 degrader for cancer therapy which is worthy of further evaluation.

Keywords: Anticancer agents; Histone methylation; Hydrophobic tagging method; PRMT6; Protein degrader.