Structure-based discovery of a new series of nucleoside-derived ring-opening PRMT5 inhibitors.

The ubiquitous methyltransferases employing SAM as the methyl donor have emerged as potential targets in many disease treatments, especially in anticancer. Therefore, developing SAM-competitive inhibitors of methyltransferases is of great interest to the drug research. To explore this direction, herein, we rationally designed a series of nucleoside derivatives as potent PRMT5 inhibitors with novel scaffold. The representative compounds A2 and A8 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other PRMTs and PKMTs. Further cellular experiments revealed that compounds A2 and A8 potently reduced the level of sDMA and inhibited the proliferation of Z-138 and MOLM-13 cell lines by inducing apoptosis. Moreover, compounds A8 which had favorable pharmacokinetic properties exhibited potent antitumor efficacy without the loss of body weight in a subcutaneous MOLM-13 xenograft model. In summary, our efforts provided a series of novel nucleoside analogs as potent PRMT5 inhibitors and may also offer a new strategy to develop SAM analogs as other methyltransferases' inhibitors.

Multifaceted anti-colorectal tumor effect of digoxin on HCT8 and SW620 cells in vitro.

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Novel drugs for CRC therapy are urgently needed. Digoxin has been in clinical use for treatment of heart failure and atrial arrhythmias for many years. Fragmentary reports suggested that digoxin might have antitumor efficacy on CRC. Here, we aimed to investigate the antitumor effect of digoxin on human CRC cells and the underlying mechanism. METHODS: Cell viability was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and plate colony formation assay. The effects of digoxin on cell-cycle distribution and apoptosis were analysed by flow cytometry. The anti-metastatic effect on tumor cells was determined by wound-healing assay and transwell assay. Anti-angiogenic effect was examined by determining the inhibition against proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). Mechanism study was performed by Western blot, enzyme-linked immunosorbent assay (ELISA), and gelatin-zymography assay. RESULTS: Digoxin potently inhibited cell proliferation, induced G1-phase and G2/M-phase arrest in colorectal-cancer HCT8 and SW620 cells, respectively. No obvious apoptosis was observed in the treated cells. Anti-metastatic activities were shown on HCT8 cells by inhibiting the migration and invasion. Meanwhile, the expression of MMP2, MMP9, and phosphorylated Integrinß1 were decreased. Digoxin inhibited the proliferation, migration, and tube formation of HUVECs and reduced HIF1α expression and vascular endothelial growth factor A (VEGF-A) secretion in HCT8 cells, suggesting anti-angiogenic activity. Furthermore, digoxin significantly reversed ABCB1-mediated multidrug resistance on SW620/Ad300 cells. CONCLUSION: Our findings suggest that digoxin has the potential to be applied as an antitumor drug via inhibiting proliferation and metastasis as well as reversing the ABCB1-mediated multidrug resistance of colorectal cancer.