As the fundamental determinant of cell fate and identity, the epigenome plays a central role in differentiation, development, and disease. Our understanding of epigenetic regulation is in its infancy and chemical biology is poised to play a central role in advancing scientific knowledge and assessing therapeutic opportunities in the field. Specifically, the creation of small molecule high-quality chemical probes that modulate the epigenome are a critical step in assessing preclinical target validity, while providing the potential for an immediate transition to a drug discovery effort.<br/><br/>Chromatin reader proteins functionally bind or interpret histone post-translational modifications to recruit protein complexes that mediate access to the underlying DNA. Considering the abundant disease associations with reader proteins that recognize methyl-lysine (Kme), ranging from cancer to neurodegeneration to viral latency, Kme reader chemical probes have the potential to establish a new class of therapeutics. The underlying mechanisms linking many of these proteins to disease remain to be defined and pharmacologic targeting is critical in determining their suitability for therapeutic intervention. We apply a target-class strategy to Kme reader antagonist development and generate focused chemical libraries and in vitro and cellular assays to discover probes for this family.<br/><br/>We have pioneered the development of inhibitors for Kme reader proteins, reporting the first chemical probe for a protein within this family (L3MBTL3). More recently we developed a peptidomimetic cellular probe targeting the chromodomains of Polycomb Repressive Complex 1 (PRC1), as the centrality of PRC activity in cancer establishes a pressing need for chemical probes that help to validate PRC components for therapeutic intervention. We are currently developing improved PRC1 chromodomain inhibitors and utilizing these tools to better understand Polycomb biology, while also exploring inhibitors for other chromodomains and families of Kme reader proteins for various biological and disease relevant applications. We hope that such novel probes will serve as invaluable reagents in validating understudied epigenetic targets with therapeutic potential for drug discovery programs, and similarly invalidating those targets that may have otherwise been pursued for good reason, yet ultimately consume massive amounts of time and resources with little productive outcome.

Promoting illiteracy: Development of chemical probes for epigenetic reader domains to explore untapped targets

2019 Spring National Meeting

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