DW14800, a PRMT5 Inhibitor, Promotes HNF4α Transcription.

DW14800 a PRMT Inhibitor Promotes HNFα Transcription 2019 08 04 - DW14800, a PRMT5 Inhibitor, Promotes HNF4α Transcription.Nowadays, liver cancer becomes more frequent among various kinds of diseases. There are many factors leading to liver cancer, such as hepatitis B, hepatitis C, or alcohol. Except for these, non-alcoholic fatty liver disease and liver flukes may cause liver cancer.

Cancer stem cells (CSCs) are cancer cells, with characteristics similar to normal stem cells. These cells undergo self-renewal and differentiate into multiple cell types. In the process, CSCs may produce tumors.

PRMT5 (Protein arginine methyltransferase 5) is a highly conserved arginine methyltransferase. It demethylates H2AR3, H4R3, H3R2, and H3R8 symmetrically, which involve a series of transcriptional activities. PRMT5 exhibits increased levels in hepatocellular carcinoma (HCC). Thus, PRMT5 becomes a target in liver cancer research. PRMT5 inhibitors have potential in the treatment of liver cancer.

Herein, we will talk about a PRMT5 inhibitor, DW14800.

DW14800 shows an IC50 of 17 nM for PRMT5. In HCCs, it reduces cellular symmetric dimethylarginine and also decreases H4R3me2s and H3R8me2s levels. Moreover, the inhibitor blocks the expression of stemness genes. Surprisingly, DW14800 also blocks the self-renewal of liver cancer stem cells via PRMT5.

In addition, DW14800 incudes apoptosis, and enhances the recovery of hepatic function in HCCs. It shows IC50s of 2.7 μM and 1.4 μM against the proliferation of Huh-7 and Hep3B cells.

Furthermore, DW14800 inhibits the mRNA and protein levels of HNF4α. It regulates the binding of H4R3me2s to the HNF4α promoter.

In brief, DW14800 is a potent PRMT5 inhibitor, exhibits anti-cancer activity.

References:
1. Zheng BN, et al. Theranostics. 2019 Apr 13;9(9):2606-2617.

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