Discovery of novel PRMT5 inhibitors bearing a methylpiperazinyl moiety

Background: 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. Methods & Results: We synthesized a series of methylpiperazinyl derivatives as novel PRMT5 inhibitors that were achieved by scaffold-hopping from EPZ015666 by virtual screening followed by rational drug design. Among all compounds 43g, 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, 43g selectively inhibited PRMT5 among protein arginine methyltransferase isoforms. Further proteomics analysis revealed that 43g remarkably reduced the global arginine dimethylation level in a cellular context. Conclusion: This work provides new chemical templates for future structural optimization of PRMT5-related cancer treatments.