AIT-102

They down-regulate gene expression in various cellular processes, including Sp1-responsive genes that control tumor development. Moreover, MTA and several mithralogs, such as EC-8042 (DIG-MSK) and EC-8105, effectively treat Ewing sarcoma by inhibiting transcription controlled by the oncogenic EWS-FLI1 transcription factor.

Overall, these data highlight the relevant role that NOTCH1 signaling plays in mediating stemness in osteosarcoma. Moreover, we demonstrate that EC-8042 is powerful inhibitor of NOTCH signaling and that the anti-CSC activity of this mithramycin analog highly rely on its ability to repress this pathway.

Accordingly, we review several methods that have been used to target SETDB1, such as using Mithramycin A, Mithralog EC-8042, 3'-deazaneplanocin A (DZNep), and paclitaxel. Finally, we conclude by highlighting remaining gaps in knowledge and challenges surrounding SETDB1. Ultimately, our review captures the wide scope of findings on SETDB1's history, function, its implications in cancer, and provides suggestions for future research in the field.

These effects occurred at concentrations not associated with DNA damage and were not due to global chromatin remodeling or widespread gene expression changes. Importantly, a single 3-day infusion of EC8042 caused dramatic regressions of RT xenografts, recapitulated the increase in H3K27me3, and cellular differentiation described in vitro to completely cure three out of eight mice.