F5446

F5446 is a small molecule inhibitor of the histone methyltransferase SUV39H1, currently under investigation for the treatment of glioblastoma (GBM). By inhibiting SUV39H1, F5446 disrupts the epigenetic silencing of transposable elements (TEs), such as LINE-1, leading to the accumulation of cytosolic double-stranded RNA (dsRNA). This induction of "viral mimicry" triggers an innate immune response characterized by the activation of interferon-stimulated genes (ISGs). Additionally, F5446 promotes replication stress and DNA damage, evidenced by increased markers such as cytosolic dsDNA, γH2AX, and phospho-RPA32. Preclinical studies in orthotopic GBM models have demonstrated that F5446 can significantly reduce tumor growth, extend survival, and remodel the tumor microenvironment by shifting tumor-resident microglia toward a pro-inflammatory phenotype.