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Research & Development

Constellation’s research is focused on each of the major pillars of epigenetic regulation – chromatin writers, erasers, and readers. Each of these protein classes provides a rich collection of targets with strong disease association. We have developed drug discovery platforms in each class to enable the development of novel medicines that modulate these important targets. Constellation has made significant progress in discovering and developing compelling drug candidates derived from our broad platform of capabilities applied to these three classes of epigenetic targets.

 

Histo ne methyltransferases (HMTs) are enzymes that catalyze the addition of methyl marks to histone proteins. These types of chemical modifications to histones impact chromatin architecture and the regulation of gene expression. Aberrant activity of HMTs is implicated in a host of human diseases, including oncology, inflammation, infection, metabolism, and neurology.

 

The discovery of the first histone demethylase (HDM) fundamentally changed the understanding of the reversibility of histone methylation. There are two families of HDMs – amine oxidases and hydroxylases – and both are implicated in human diseases, including cancer, inflammation, and metabolic disease.

Readers are proteins that bind to specific recognition domains, typically methyl or acetyl marks, on chromatin in a highly regulated manner. These chromatin-binding events result in the modulation of chromatin architecture, which impacts gene expression and are ultimately implicated in key cellular processes such as cell cycle progression, cytokine signaling, and viral integration.

The company's research into chromatin readers recently appeared in the Proceedings of the National Academy of Sciences. Constellation scientists demonstrated that MYC transcription can be suppressed using small molecule inhibitors of the BET family of chromatin inhibitors. MYC is a master regulator of diverse cellular functions and has long been considered a compelling therapeutic target because of its role in many human malignancies.