Features | Partner Sites | Information | LinkXpress
Sign In
JIB
BioConferenceLive
GLOBETECH PUBLISHING

Novel Chemical Probe Targets Malignant Brain Tumor Genome

By BiotechDaily International staff writers
Posted on 14 Mar 2013
Image: The chemical probe UNC1215 will be used to investigate the function of malignant brain tumor-domain protein, L3MBTL3, and study its role in different signaling pathways and disease (Photo courtesy of Frye Lab, University of North Carolina).
Image: The chemical probe UNC1215 will be used to investigate the function of malignant brain tumor-domain protein, L3MBTL3, and study its role in different signaling pathways and disease (Photo courtesy of Frye Lab, University of North Carolina).
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.

Related Links:
University of North Carolina



comments powered by Disqus

Channels

Drug Discovery

view channel
Image: A mouse mammary gland missing the tumor-suppressor p53 shows expression of ARF (green), now known for a backup role in protecting cells from becoming cancerous. If both p53 and ARF are mutated, the tumors that form are aggressive and may benefit from treatment with anti-inflammatory drugs called JAK inhibitors, currently prescribed for rheumatoid arthritis (Photo courtesy of Raleigh Kladney).

Anti-Inflammatory Drugs May Treat Some Aggressive Rumors

New research raises the possibility that some cancer patients with aggressive tumors may benefit from a class of anti-inflammatory drugs used to treat rheumatoid arthritis. By studying triple-negative... Read more

Therapeutics

view channel

Vaccine Being Developed for Heart Disease Close to Reality

The world’s first vaccine for heart disease is becoming a possibility with researchers demonstrating significant arterial plaque reduction in concept testing in mice. Klaus Ley, MD, from the La Jolla Institute for Allergy and Immunology (LA Jolla, CA, USA), and a vascular immunology specialist, is leading the vaccine... Read more

Business

view channel

A Surge in IPOs Revitalize Investments for the Global Pharma and Biotech

Anti-infective drugs, oncology, and pharmaceutical contract laboratories attract the most investment up to now. The intensified private equity and venture capital (PEVC) deal activity in the global healthcare industry during the recession years, 2008–2010, witnessed a waning post-2010. However, the decline in deals... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.