SG-8

SG-8 is a novel, brain-penetrant small molecule inhibitor of the Polycomb Repressive Complex 2 (PRC2), specifically targeting the subunits Enhancer of Zeste Homolog 2 (EZH2) and Embryonic Ectoderm Development (EED). It was designed as a derivative of TDI-6118 to address the poor blood-brain barrier permeability of first-generation EZH2 inhibitors like Tazemetostat, making it a candidate for treating melanoma brain metastases. SG-8 demonstrates anti-tumor activity by reducing EED and EZH2 protein levels and inhibiting the Akt-EZH2 signaling axis, evidenced by decreased phosphorylation of Akt (Ser473) and EZH2 (Ser21). In preclinical models, SG-8 has shown efficacy against both primary and metastatic human malignant melanoma cells.