G9a/GLP degrader (Osaka University)

G9a and G9a-like protein (GLP) are histone methyltransferases that regulate epigenetics by adding methyl groups to histone H3, thereby controlling gene expression. G9a/GLP dysregulation and overexpression have been reported to cause cancer proliferation, progression, and metastasis. So far, quinazoline-based inhibitors and degraders have been frequently used as chemical tools to elucidate the role of G9a/GLP. However, quinazoline-based inhibitors exhibit toxicity in normal cells. In this context, we identified a G9a/GLP degrader (4) based on RK-701, a less-toxic G9a/GLP-selective inhibitor. Compound 4 effectively decreased G9a/GLP protein levels and methylated histone levels in breast cancer MCF-7 cells without inhibiting the cell viability, similar to G9a small interfering RNA (siRNA). Furthermore, again similar to G9a siRNA, the degradation of G9a/GLP by 4 inhibited the migration of MCF-7 cells. These results suggest potential for 4 to serve as a valuable tool for investigating the G9a/GLP biology and as a lead compound for drug discovery.