Discovery and Characterization of Chemical Tools for Chromatin and Kinase Biology

Validation of potential therapeutic targets is an important first step in expanding the number of druggable targets. The development of chemical tools and chemical probes is a critical activity due to the contribution they can make to target validation and the discovery of small molecule drugs which have >90% market share of prescription medicines. Epigenetic and kinase targets are particularly appealing as they can be harnessed by cancer and/or infectious disease to facilitate disease progression. Several epigenetic proteins including readers, writers, and erasers play important roles in transcription, replication, and DNA repair. Readers, proteins that bind epigenetic marks, are relatively understudied in comparison to their writer and eraser counterparts that deposit and remove the post translational marks. Through various screening strategies including high-throughput screening of focused libraries as well as screening of diverse DNA-Encoded libraries, medicinal chemistry optimization, and chemical biology techniques we seek to expand our toolbox of antagonists of readers of methylated lysine. Herein, we report the discovery of novel antagonists for epigenetic reader proteins CHD1 and PHF19 with promising implications in prostate cancer and multiple myeloma respectively as well as a degrader of the STING kinase capable of dampening the innate immune response.