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
  • 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: [email protected].
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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