Synthesis and Evaluation of Aryloxy-Acetamide Derivatives as CBX2 Inhibitors

The CBX2 protein plays a key role in the methylation of histone lysine residues related to epigenetic silencing. In contrast to other polycomb paralogs, there are few examples of CBX2 modulators, which prompted us to develop small-molecule CBX2 inhibitors by synthetic evolution based on virtual screening hit scaffolds previously reported by our group. We synthesized a series of aryloxy-acetamide derivatives and evaluated their CBX2 inhibitory activities using the NanoBRET assay and the subsequent NanoBiT assay. Through structural modifications, compound 16 was identified as the best CBX2 inhibitor in this series.