PRMT5 is an epigenetics-related enzyme, which plays a critical role in cancer development. Hence PRMT5 inhibition has been validated as a promising therapeutic strategy. We synthesized a series of methylpiperazinyl derivatives as novel PRMT5 inhibitors that were achieved by scaffold-hopping from by virtual screening followed by rational drug design. Among all compounds , bearing a thiourea linker, showed antitumor activity across multiple cancer cell lines and reduced the level of symmetric arginine dimethylation of SmD3 dose-dependently. Moreover, selectively inhibited PRMT5 among protein arginine methyltransferase isoforms. Further proteomics analysis revealed that remarkably reduced the global arginine dimethylation level in a cellular context. This work provides new chemical templates for future structural optimization of PRMT5-related cancer treatments.
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