Chemical Tool Development to Enable Target Validation of Methyl-Lysine Reader Proteins

Recent advances in our understanding of epigenetic reader proteins and their role in disease pathology has engendered a need for the development of chemical probes to enable target validation studies in this area. Unlike writer and eraser enzymes that deposit and remove histone post-translational modifications, respectively, reader proteins bind histone marks to recruit effector proteins and thereby enable chromatin remodeling and regulation of transcription and DNA damage repair. Despite their central role in chromatin regulation, readers are a relatively unexplored class of proteins in terms of therapeutic potential. Chemical probe antagonists against readers will provide a complementary approach to genetic targeting methods and allow researchers to identify and assess opportunities for therapeutic intervention. Our lab employs a protein target-class approach to develop antagonists and chemical degraders of methyl-lysine (Kme) readers. We use a combination of focused small molecule and fragment library screening, biochemical and biophysical assays, and medicinal chemistry to guide our efforts. Herein, we report cellular permeability assessments of PROTACs to guide chemical degrader optimization for Kme reader target EED and initial chemical probe development for two Kme reader targets, 53BP1 and KDM7B.