Abstract

Small Molecule Inhibitors of an Epigenetic Eraser Family

Danica Fujimori, Principal Investigator, University of California San Francisco

Development of tool compounds for jumonji histone demethylases, a class of epigenetic eraser proteins, is necessary for understanding the role of these enzymes in cellular physiology and pathogenesis of diseases with aberrant chromatin methylation status. Elevated expression of KDM4 is thought to promote oncogenesis in several cancers, including prostate, breast and colon cancer. To discover inhibitors of this enzyme family, we docked a library of 600,000 fragment molecules into a high-resolution crystal structure of KDM4A. 5-Aminosalicylates emerged among the most interesting chemotypes. Interestingly, these molecules docked in two distinct but overlapping orientations. Docking poses of aminosalicylates informed a fragment linking strategy, which was followed by derivatization. This combined approach improved the affinity by ~3 log-orders yielding hybrid compounds with nanomolar potencies (Ki = 43 nM). Hybrd inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A and KDM6B, while lacking selectivity against KDM3 and KDM5 subfamilies. Obtained crystal structures confirmed docking poses. Our work extends the use of structure-based docking and fragment linking to yield potent demethylase inhibitors.