Novel Chemical Probe Targets Malignant Brain Tumor Genome

The development of a chemical probe that specifically targets the L3MBTL3 methyl-lysine reader domain will enable cancer researchers to investigate the function of malignant brain tumor (MBT) domain proteins in biology and disease.

L3MBTL3 (lethal(3)malignant brain tumor-like protein 3), which is required for normal maturation of myeloid progenitor cells, is a Polycomb group (PcG) protein. PcG proteins are a family of proteins first discovered in fruit flies that can remodel chromatin so that epigenetic silencing of genes takes place. In humans Polycomb Group gene expression is important in many aspects of development. Mouse mutants lacking PRC2 (Polycomb Repressive Complex 2) genes die as embryos while most PRC1 (Polycomb Repressive Complex 1) mutants are born alive but with anatomic rearrangements that cause them to die shortly after birth. In contrast, overexpression of PcG proteins correlates with the severity and invasiveness of several cancer types.

A recent paper by investigators at the University of North Carolina (Chapel Hill, USA) described the use of the novel chemical probe UNC1215 for research on L3MBTL3. UNC1215 is a potent and selective chemical probe for the Kme reading function of L3MBTL3. Kme (methyl-lysine) recognition domains play a central role in epigenetic regulation during cellular differentiation, development, and gene transcription with more than 200 known “reader” domains in the human proteome. UNC1215 binds the MBT domains of L3MBTL3 and competitively displaces mono- or dimethyl-lysine containing peptides. This probe is greater than 50-fold more selective towards L3MBTL3 than towards other members of the human MBT family and also demonstrates selectivity against more than 200 other Kme reader domains.

Results obtained by X-ray crystallography published in the March 2013 issue of the journal Nature Chemical Biology revealed a unique 2:2 polyvalent mode of interaction between UNC1215 and L3MBTL3. In cells, UNC1215 was found to be nontoxic and bound to L3MBTL3 via the Kme-binding pocket of the MBT domains.

"Before this there were no known chemical probes for the more than 200 domains in the human genome that recognize methyl lysine. In that regard, it is a first in class compound. The goal is to use the chemical probe to understand the biology of the proteins that it targets," said first author Dr. Lindsey James, research assistant professor of chemical biology and medicinal chemistry at the University of North Carolina.

To promote research on the biology of malignant brain tumors the University of North Carolina will provide investigators with samples of UNC1215 free of charge on request.

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