Recent research has shown numerous mechanisms of genetic regulation to exist through covalent changes of the Histone tail.  Lysine can exist in three different methylation states and each triggers a unique protein-protein interaction.  Increasingly these interactions are being implicated as factors in the increased proliferation and invasiveness of numerous cancers.  My research focuses on chemical inhibitors of this interaction.  By antagonizing both sides of this important protein-protein interaction we hope to better understand this important cancer pathway.  To accomplish this goal I have begun the design, synthesis and in vitro testing of these novel inhibitors against their native binding partners.   Through mimicry of the protein binding pocket I have studied the first known inhibitor of this trimethyllysine-dependant interaction.  With this initial result I have begun the synthesis of a new class of macrocyclic compounds to enhance potency and selectivity.  In a fragment-based screen, numerous small quaternary ammonium cations have been synthesized and tested against a native trimethyllysine binding partner in vitro.  The next generation of these findings will be discussed.

Design, synthesis and evalulation of small molecule H3K27me3-recognition protein inhibitors

243rd National Meeting (2012)

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