OCT 29, 2014 9:00 AM PDT

Reading and disrupting the histone code with chemical agents: making new tools to understand epigenetic methylation pathways in stem-like cancers

Speaker
  • Associate Professor, University of Victoria
    Biography
      Fraser was born in 1976, raised in Medicine Hat, Alberta, and got his start in chemistry with a B.Sc. at the University of Alberta. In 1998 he moved to warmer climes at the Scripps Research Institute in La Jolla, California to study supramolecular chemistry with Julius Rebek, Jr. After obtaining his Ph.D. at Scripps, he was a Novartis Foundation (2003) and Human Frontier Science Program (2004) post-doctoral fellow studying medicinal chemistry in the labs of Franois Diederich at the Swiss Federal Institute of Technology (ETH-Zurich). Finally returning home to western Canada, he took up his position at the University of Victoria in 2005. Frasers research program creates new chemical tools for studying and disrupting epigenetic stem cell regulation, with the goals of understanding the basic mechanism of epigenetic programming of stem cells, and of creating new treatments for the most aggressive, stem-like cancers of prostate, breast, and blood.

    Abstract

    Post-translational methylations play central roles in epigenetic gene regulation pathways that are central to stem cell regulation. Lysine methylations are turn-on switches for hundreds of distinct protein-protein interactions among a diverse family of cell regulators called epigenetic reader proteins. In spite of their biological importance and relevance to therapeutic development, there exist few synthetic agents that can help us to study or antagonize these pathways. We have been developing chemicals that can mimic, sense, or antagonize the lysine-methylation-driven biochemistry important to healthy and disease-linked cellular processes. We have created organic macrocycles that can recognize and bind to methylated sites on proteins, including examples that disrupt methylation-driven protein-protein interactions and others that can provide a readout of a proteins methylation state. We have also targeted a family of methylation reader proteins called chromodomains, having created antagonists of the epigenetic master controller Chromobox homolog 7 (CBX7) that is a master controller of stem cell programming. We will report on the impacts of these new inhibitors on the programming of cancer cells and stem-like cancer cells, and discuss implications for developing new treatments for stem-like cancers that tend to have the most aggressive and untreatable clinical manifestations.


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