The cellular epigenetic machinery (writers, erasers and readers) contribute to the transcriptional control of genes without affecting the underlying DNA sequence. Epigenetic marks imparted by the writers (methyl and acetyl transferases) can lead to the transcription or repression of genes. When these events are aberrant they can lead to cancer progression and may be targeted with disease-modifying inhibitors. The validity of multiple epigenetic oncology targets has been established in clinical trials [histone deacetylase (HDAC) and DNA-methyl transferase (DNMT) inhibitors] and several additional targets are under investigation (PRC2, DOT1L and BET). The polycomb repressive complex 2 (PRC2) comprises five core components and is responsible for the methylation of histone 3 at lysine 27 (H3K27). Trimethylation of histone 3 (H3K27Me3) silences the transcription of various tumor suppressor genes, which in turn, regulates cellular growth and differentiation in a tightly regulated manner. The dysregulation of PRC2 by mutation of its components or alteration of chromatin remodeling pathways (e.g., SWISNF) can result in malignant transformation of certain cell types. There are several studies underway that examine inhibition of the catalytic site housed within the enhancer of zeste homolog 2 (EZH2) subunit of the PRC2 complex. More recently, an allosteric inhibition site within the PRC2 EED subunit has been explored. We will describe a structure-based approach toward an early lead molecule designed to interact with a unique binding conformation of lysine 211 within the EED protein. The initial imidazopyrimidine lead compound was neither highly soluble nor metabolically stable <i>in vitro</i>. Here, we illustrate the discovery of that lead compound and its optimization to provide a selective and orally efficacious EED-binding inhibitor of the PRC2 complex.

Novel imidazopyrimidine binders to embryonic ectoderm development (EED) protein that inhibit polycomb repressive complex 2 (PRC2) activity

2019 Fall National Meeting

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