SET7 is a protein lysine methyltransferase (PKMT), which methylates a plethora of proteins and regulates diverse biological processes. Meanwhile, SET7 plays a significant role in transcriptional regulation, cell cycle control, differentiation, DNA repair, and DNMT1 stability. Specifically, researches show that SET7 is closely associated with various diseases. Particularly, SET7 regulates NF-κB activity through lysine monomethylation of p65 in response to TNF-α in human kidney cells, and knockdown of SET7 inhibits key NF-κB-dependent gene expression. Recently, research shows that epigenetic changes induced by SET7 contribute to vascular dysfunction in patients with type 2 diabetes. In addition, the downregulation of SET7 in breast cancer cells attenuates estrogen-induced gene activation. Besides, SET7 knockdown results in a concomitant decrease in the steady-state levels of estrogen receptor α (ERα) protein, which is involved in the pathology of breast cancer, endometrial cancer, and osteoporosis. As SET7 is a promising target in several diseases, including diabetes, alopecia areata, cancers, and virus infection, so it is important to find a potent SET7 inhibitor.

DC-S239 is a Selective SET7 Inhibitor With Anti-Cancer Activity.

DC-S239 is a selective histone methyltransferase SET7 inhibitor with an IC₅₀ value of 4.59 μM. Meanwhile, DC-S239 also shows selective on DNMT1, DOT1L, EZH2, NSD1, SETD8 and G9a. This compound inhibits the activity of DNMT1, DOT1L, EZH2, NSD1, SETD8 and G9a by less than 45%, while it inhibits SET7 by 90% at concentrations of 100 μM. Moreover, DC-S239 (0-100 μM, 120 h) shows antiproliferative activity for MCF7, HL60 cells with the IC₅₀ values of 10.93 μM and 16.43 μM, respectively. But shows no significant effect on the activity of HCT116 and DHL4 cells. In conclusion, DC-S239 is a potent and selective SET7 Inhibitor and shows antiproliferative activity for some cancer cells.