A Novel PROTAC G9a/GLP Degrader that Inhibits, Similar to G9a siRNA, the Migration of MCF‑7 Breast-Cancer Cells without Affecting Proliferation

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.