September
21,
2018
Stephen Frye, PhD
Fred Eshelman Distinquished Professor
Director, Center for Integrative Chemical Biology & Drug Discovery
Eshelman School of Pharmacy
University of North Carolina
Host: Medicinal Chemistry Center
Methyl-lysine (Kme) recognition domains play a central role in chromatin regulation during cellular differentiation, development, and gene transcription with more than 200 known Kme “reader” domains described in the human proteome. Our research focuses on the discovery of potent and well characterized, cellularly active chemical probes of Kme readers. The advantages of a small molecule driven approach to modulating chromatin biology are numerous: temporal resolution; mechanistic flexibility (targeting a specific activity of a protein as opposed to ablating them all with transgenic knock-outs or genetic interference/editing techniques); ease of delivery; and most significantly, when warranted, a small molecule tool has the potential to provide an immediate transition to a drug discovery effort, potentially cutting years off the time between target validation and therapeutic intervention. I will describe our overall target-class approach to ligand design and discovery for Kme readers and the discovery of a chemical probe (UNC3866) for the Polycomb repressive complex 1 CBX Kme reader domains.
