Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease...

The discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC₅₀ = 0.024 μM). X-ray crystallography for the ligand-protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of γ-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner.