Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy-quinazolines

Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most potent G9a inhibitor to date, via structure-based design and structure-activity relationship (SAR) exploration of the quinazoline scaffold represented by BIX01294 (1). Despite its very high in vitro potency, compound 3 lacks sufficient cellular potency. The design and synthesis of several generations of new analogues aimed at improving cell membrane permeability while maintaining high in vitro potency resulted in the discovery of a number of novel G9a inhibitors such as UNC0646 (6) and UNC0631 (7) with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity. The design, synthesis, and cellular SAR of these potent G9a inhibitors are described.