Abstact

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 (IC(50) <2.5 nM), we successfully transformed it into a selective PRMT4 inhibitor AK442 (IC(50) = 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.