Abstract

Academic Drug Discovery: Progress Towards High-quality Chemical Probes of Methyl-Lysine Readers for Target Validation

Stephen Frye, Director, University of North Carolina

While academic science has always provided fundamental understanding of the biological and clinical basis of disease, the opportunity and imperative for academics to contribute more directly to the discovery of new medicines continues to grow. The creation of high-quality chemical probes for novel targets is an especially impactful arena for academic research. The primary intent of a chemical probe is to establish the relationship between a molecular target, usually a protein whose function is modulated by the probe, and the biological consequences of that modulation. In order to fulfill this purpose, a chemical probe must be profiled for selectivity, mechanism of action, and cellular activity, as the cell is the minimal system in which ‘biology’ can be explored. Methyl-lysine recognition domains (Kme readers) play a central role in chromatin regulation during cellular differentiation, development, and gene transcription with more than 200 known Kme reader domains in the human proteome. I will describe our target-class approach to ligand design and discovery for three disease relevant members of this large family: L3MBTL3 (a Malignant Brain Tumor (MBT) domain containing reader), 53BP1 (a tandem Tudor domain) and CBX7 (a chromo domain). The pursuit of high quality chemical probes for Kme reader proteins represents an emerging area that will open new avenues of research in chromatin biology and may in time, translate to new therapeutic approaches.