The dynamic relationship between the multiprotein Polycomb group (PcG) complexes, Polycomb repressive complex 1 (PRC1) and PRC2, plays a critical role in regulating the propagation of repressive histone marks on chromatin. PcG protein misregulation and overexpression has been implicated in diseases such as cancer, and consequently much effort has been put forth in recent years to manipulate PRC function with small molecule inhibitors. As a complementary approach, we are exploring the selective degradation of PcG complex components to decipher the biological mechanism within these diseases.<br/>Protein degradation using proteolysis targeting chimeras (PROTACs) is a valuable approach for difficult targets within drug discovery. For example, PROTACs can selectively degrade proteins when derived from promiscuous small molecule inhibitors and because degradation is believed to be catalytic a lower intracellular compound concentration may be necessary compared to small molecule inhibitors. Utilizing known PRC inhibitors, which can be functionalised with appropriate PEG linkers and E3 ligase recruiters, we aim to establish a chemical toolbox of polycomb-directed PROTAC reagents.

Towards the design of proteolysis targeting chimeras (PROTACs) for the degradation of polycomb group proteins

256th National Meeting (2018)

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