Design, Synthesis, and Biological Evaluation of 3,4-Dihydroisoquinolin-1(2H)-one Derivatives as Protein Arginine Methyltransferase 5 Inhibitors for the Treatment of Non-Hodgkin’s Lymphoma

Through catalyzing the transfer of methyl groups onto the guanidinium of arginine, protein arginine methyltransferase 5 (PRMT5) was essential to the cell growth of cancer cells. By utilizing a scaffold hopping strategy, a novel series of 3,4-dihydroisoquinolin-1(2H)-one derivatives were designed and synthesized. Through a systematic SAR study, D3 demonstrated excellent PRMT5 inhibitory activity, potent antiproliferative activity against Z-138, favorable pharmacokinetic profiles, and low hERG toxicity. Molecular docking, molecular dynamic (MD) simulation, and surface plasmon resonance (SPR) study indicated that D3 was tightly interacted with PRMT5. Meanwhile, D3 exhibited high selectivity against PRMT5, which could inhibit the growth of various cancer cells, induce apoptosis, and arrest the cell cycle in the G0/G1 phase. Additionally, D3 possessed excellent antitumor efficacy in Z-138 xenograft models, low toxicity in vivo, and acceptable drug metabolism and pharmacokinetics (DMPK) profiles in vitro. Therefore, D3 can be developed as a promising candidate for the treatment of non-Hodgkin's lymphoma (NHL).