Discovery of Novel PRMT5 Inhibitors by Virtual Screening and Biological Evaluations

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  • Tao Hongrui
    School of Chemistry and Chemical Engineering, University of Jinan Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
  • Yan Xue
    School of Chemistry and Chemical Engineering, University of Jinan
  • Zhu Kongkai
    School of Biological Science and Technology, University of Jinan
  • Zhang Hua
    School of Biological Science and Technology, University of Jinan

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<p>As an important epigenetics related enzyme, protein arginine methyltransferase 5 (PRMT5) has been confirmed as an anticancer therapeutic target in recent years. Among all the reported PRMT5 inhibitors, two small molecules (GSK-3326595 and JNJ-64619178) are currently being assessed in clinical trial. In this study, 40 PRMT5 inhibitor candidates were purchased from SPECS database supplier according to the pharmacophore and molecular docking based virtual screening results. Alpha linked immunosorbent assay (LISA) methylation assay was performed to test their inhibitory activity against PRMT5. The in vitro enzymatic assay results indicated that four compounds (2, 4, 10 and 37) showed PRMT5 inhibitory activity, while 4 and 10 displayed the most potent activity with IC50 values of 8.1 ± 1.1 and 6.5 ± 0.6 µM, respectively. The inhibitory activity results of 20 extra analogs of 4 further confirmed the potency of this scaffold. As expected, compounds 4 and 10 exhibited moderate anti-proliferative activity against mantle cell lymphoma Jeko-1 and leukemia cell MV4-11. Besides, Western blot assay results showed that 4 could reduce the H4R3me2s level in a dose-dependent manner, indicating that it could inhibit the activity of PRMT5 in cellular context. Detailed interactions between 4 and PRMT5 were characterized by binding mode analysis through molecular docking. The compounds discovered in this study will inspire medicinal chemists to further explore this series of PRMT5 inhibitors.</p>

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