Opto-Epigenetic Regulation of Histone Arginine Asymmetric Dimethylation via Type I Protein Arginine Methyltransferase Inhibition

  • J Med Chem. 2025 Feb 27;68(4):4373-4381. doi: 10.1021/acs.jmedchem.4c02199.
Shuting Xu  1  2  3 ,  Kaiqi Long  1  2  3 ,  Tianyi Wang  1  2  3 ,  Yangyang Zhu  4  5 ,  Yunjiao Zhang  4  5 ,  Weiping Wang  1  2  3
Affiliations
  • 1. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong 999077, China.
  • 2. Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China.
  • 3. Laboratory of Molecular Engineering and Nanomedicine, Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong 999077, China.
  • 4. The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China.
  • 5. School of Biomedical Sciences and Engineering, National Engineering Research Center for Tissue Restoration and Reconstruction and Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou 510006, P. R. China.
PMID: 39961800 DOI: 10.1021/acs.jmedchem.4c02199
Abstract

Histone arginine asymmetric dimethylation, which is mainly catalyzed by type I protein arginine methyltransferases (PRMTs), is involved in broad biological and pathological processes. Recently, several type I PRMT inhibitors, such as MS023, have been developed to reverse the histone arginine dimethylation status in tumor cells, but extensive inhibition of type I PRMTs may cause side effects in normal tissues. Herein, we designed a photoactivatable MS023 prodrug (C-MS023) to achieve spatiotemporal inhibition of histone arginine asymmetric dimethylation. In vitro studies showed that C-MS023 exhibited reduced potency in inhibiting type I PRMTs. Importantly, visible light irradiation at 420 nm could trigger the photolysis of the prodrug, thereby liberating MS023 for effective downregulation of histone arginine asymmetric dimethylation and DNA replication-related transcriptomic activities. This opto-epigenetic small-molecule prodrug potentially aids in further research into the pathophysiological functions of type I PRMTs and the development of targeted epigenetic therapeutics.

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