Jacob Stuckey (PhD Candidate 2016) and colleagues report in Nature Chemical Biology the first cellularly active chemical probe (UNC3866) for any member of the chromodomain family of proteins that recognize, or “read” methylated lysine. Specifically, the probe inhibits the CBX chromodomains that participate in Polycomb repressive complex 1 (PRC1) and facilitate PRC1-mediated transcriptional repression by targeting the complex to the H3K27me3 mark. PRC1 is one of the major regulatory complexes involved in repression of gene transcription, and as such, plays a central role in differentiation and development. Importantly, the probe has been extremely well characterized via structural biology and selectivity studies, as well as biochemically. Lindsey James, Assistant Professor and co-corresponding author on the study with Stephen Frye, commented, “The high-quality small molecule probes have proven to be excellent tools for improving our understanding of the biological consequences of modulating their targets, and we hope that making such a tool available to the scientific community will enable a better understanding of the role of specific CBX proteins in different cancer types, while also having the potential to serve as a stepping stone towards a new class of cancer therapeutics.”
Read the Lineberger Comprehensive Cancer Center article here.