2. Academic Validation
  3. An Adenosine Analogue Library Reveals Insights into Active Sites of Protein Arginine Methyltransferases and Enables the Discovery of a Selective PRMT4 Inhibitor

An Adenosine Analogue Library Reveals Insights into Active Sites of Protein Arginine Methyltransferases and Enables the Discovery of a Selective PRMT4 Inhibitor

  • J Med Chem. 2024 Oct 24;67(20):18053-18069. doi: 10.1021/acs.jmedchem.4c01041.
Youchao Deng 1,  Eui-Jun Kim 2,  Xiaosheng Song 3,  Akshay S Kulkarni 1,  Ryan X Zhu 2,  Yidan Wang 2,  Michelle Bush 4,  Aiping Dong 3,  Nicholas Noinaj 4,  Jinrong Min 3 5,  Wei Xu 2,  Rong Huang 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States.
  • 2 McArdle Laboratory for Cancer Research, UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
  • 3 Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 4 Department of Biological Sciences, Markey Center for Structural Biology, and the Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, Indiana 47907, United States.
  • 5 Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, PR China.
PMID: 39361813 DOI: 10.1021/acs.jmedchem.4c01041
Abstract

Protein arginine methyltransferases (PRMTs) represent promising drug targets. However, the lack of isoform-selective chemical probes poses a significant hurdle in deciphering their biological roles. To address this issue, we devised a library of 100 diverse adenosine analogues, enabling a detailed exploration of the active site of PRMTs. Despite their close homology, our analysis unveiled specific chemical trends unique to the individual members. Notably, compound YD1130 demonstrated over 1000-fold selectivity for PRMT4 (IC50 < 0.5 nM) over a panel of 38 methyltransferases, including the Other PRMTs. Its prodrug YD1342 exhibited potent inhibition on cellular substrate methylation, breast Cancer cell colony formation, and tumor growth in the animal model, surpassing or matching known PRMT4-specific inhibitors. In summary, our focused library not only illuminates the intricate active sites of PRMTs to facilitate the discovery of highly potent and isoform-selective probes but also offers a versatile blueprint for identifying chemical probes for Other methyltransferases.

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