2. Academic Validation
  3. Discovery of a first-in-class degrader for the protein arginine methyltransferase 6 (PRMT6)

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.
Hongling Yang 1,  Qiangsheng Zhang 1,  Shuyan Zhou 1,  Zuli Hu 1,  Qing Tang 2,  Zulong Li 1,  Qiang Feng 3,  Luoting Yu 4
Affiliations

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.

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