Discovery of novel PRMT5 inhibitors bearing a methylpiperazinyl moiety

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...

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Bibliographic Details
Published in:Future medicinal chemistry 2022-07, Vol.14 (14), p.1071-1086
Main Authors: Bai, Xinyu, Zhai, Zheng, Zhao, Xuyang, Li, Ridong, Liang, Ling, Jin, Yan, Yin, Yuxin
Format: Article
Language:English
Subjects:
antitumor
arginine dimethylation
ligand-based drug design
PRMT5 inhibitor
structure-based drug design
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Summary: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.
ISSN:1756-8919
1756-8927
DOI:10.4155/fmc-2021-0244