Arginine Methyltransferase 5 (PRMT5) Inhibitors with 3-(1H-benzo[d]imidazol- 2-yl)anilines Core Identified by Virtual Screening and Biological Evaluation.

BACKGROUND

PRMT5 is a major enzyme responsible for the post-translational symmetric demethylation of protein arginine residues, which has been validated as an effective therapeutic target for cancer. Thus, many nucleoside-based PRMT5 inhibitors have been reported in the past year.

OBJECTIVE

To discover a novel series of non-nucleoside PRMT5 inhibitors through a molecular docking-based virtual screening approach.

METHODS

Our in-house compound library was virtually screened using the Glide program, identifying a new PRMT5 inhibitor 1. Based on the structural similarity of hit 1, a series of structure-oriented derivatives, including 3a-3e, 7a-7g, and 12a-12f, were synthesized and selected for the inhibitory activity evaluation against PRMT5, as well as cytotoxicity against MV4-11 cell.

RESULTS

The analogs 7a-7e with benzimidazole core exhibited potent PRMT5 inhibitory activities, with 7e displaying the most potent activity with an IC of 6.81 ± 0.12 μM. In the anti-proliferative assay, compound 7e showed a strong inhibitory effect on MV4-11 cell growth. Finally, the binding mode of 7e with PRMT5 was predicted to provide insights for further structural optimization.

CONCLUSION

The newly discovered PRMT5 inhibitors have potential antitumor activity against MV4-11 cells. This work highlighted this series of 3-(1H-benzo[d]imidazol-2-yl)aniline derivatives as novel anti-cancer lead compounds targeting PRMT5, which were worthy of further investigation.