Design, Synthesis,\nand Biological Evaluation of 3,4-Dihydroisoquinolin-1(<i>2H</i>)‑one Derivatives as Protein Arginine Methyltransferase\n5 Inhibitors for the Treatment of Non-Hodgkin’s Lymphoma

Through\ncatalyzing the transfer of methyl groups onto the guanidinium\nof arginine, protein arginine methyltransferase 5 (PRMT5) was essential\nto the cell growth of cancer cells. By utilizing a scaffold hopping\nstrategy, a novel series of 3,4-dihydroisoquinolin-1­(<i>2H</i>)-one derivatives were designed and synthesized. Through a systematic\nSAR study, <b>D3</b> demonstrated excellent PRMT5 inhibitory\nactivity, potent antiproliferative activity against Z-138, favorable\npharmacokinetic profiles, and low hERG toxicity. Molecular docking,\nmolecular dynamic (MD) simulation, and surface plasmon resonance (SPR)\nstudy indicated that <b>D3</b> was tightly interacted with PRMT5.\nMeanwhile, <b>D3</b> exhibited high selectivity against PRMT5,\nwhich could inhibit the growth of various cancer cells, induce apoptosis,\nand arrest the cell cycle in the G0/G1 phase. Additionally, <b>D3</b> possessed excellent antitumor efficacy in Z-138 xenograft\nmodels, low toxicity <i>in vivo</i>, and acceptable drug\nmetabolism and pharmacokinetics (DMPK) profiles <i>in vitro</i>. Therefore, <b>D3</b> can be developed as a promising candidate\nfor the treatment of non-Hodgkin’s lymphoma (NHL).