2. Academic Validation
  3. Tailoring PRMT Inhibition: Shifting PRMT7 Selectivity to PRMT4 through "T-Shape" Strategy and "Linker-Specific" Preferences

Tailoring PRMT Inhibition: Shifting PRMT7 Selectivity to PRMT4 through "T-Shape" Strategy and "Linker-Specific" Preferences

  • J Med Chem. 2026 May 14;69(9):9977-9990. doi: 10.1021/acs.jmedchem.5c01782.
Akshay S Kulkarni 1,  Youchao Deng 1,  Hye Seung Nam 1,  Tianqi Zhao 1,  Dattatraya P Masal 1,  Marlyn Michelle Bush 2,  Nicholas Noinaj 2,  Rong Huang 1
Affiliations

Affiliations

  • 1 Borch Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States.
  • 2 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.
PMID: 42066234 DOI: 10.1021/acs.jmedchem.5c01782
Abstract

Protein arginine methyltransferases (PRMTs) are appealing therapeutic targets due to their critical roles in regulating numerous cellular processes and their dysregulation in various diseases. Although SAH-based inhibitors effectively target PRMTs, achieving selectivity across different methyltransferases remains a significant challenge. Herein, we employed a hybrid strategy that incorporates optimal linker length and "T-shape" modifications to enhance inhibitor selectivity. Starting with a selective PRMT7 Inhibitor SGC8158 (IC50 <2.5 nM), we successfully transformed it into a selective PRMT4 Inhibitor AK442 (IC50 = 2.6 nM). This approach highlights the potential of these design strategies to tune inhibitor selectivity, facilitating the development of isoform-specific PRMT inhibitors from existing scaffolds.

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