The Polycomb Repressive Complex 2 (PRC2) is a transcriptional repressor that regulates several crucial developmental and physiological processes in the cell. Recently, scientists have identified a strong link between PRC2 and cancer; several cancer types exhibit dysregulation and dysfunction of PRC2 proteins. For example, PRC2 overexpression has been linked to breast cancer, prostate cancer and melanomas, and high levels of PRC2 were shown to correlate with an aggressive and advanced disease state in each of these cancer types. As a result, substantial efforts have been devoted to developing PRC2 inhibitors as cancer therapeutics, the vast majority of which are small molecules targeting the ...

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The Polycomb Repressive Complex 2 (PRC2) is a transcriptional repressor that regulates several crucial developmental and physiological processes in the cell. Recently, scientists have identified a strong link between PRC2 and cancer; several cancer types exhibit dysregulation and dysfunction of PRC2 proteins. For example, PRC2 overexpression has been linked to breast cancer, prostate cancer and melanomas, and high levels of PRC2 were shown to correlate with an aggressive and advanced disease state in each of these cancer types. As a result, substantial efforts have been devoted to developing PRC2 inhibitors as cancer therapeutics, the vast majority of which are small molecules targeting the active site. Preliminary studies have shown that inhibition of PRC2 decreases tumour growth and invasivness, which highlights the potential benefits of PRC2 inhibitors for cancer treatment. Moreover, PRC2 inhibitors have shown promise in the treatment of multiple-drug resistant cancers and cancers that have no effective treatment currently, including bladder cancer and ovarian clear cell carcinoma. Despite these promising results, however, current therapeutic approaches for targeting PRC2 have significant limitations, including susceptibility to resistance, off-target effects, and toxicity. Thus, there remains a critical need to develop PRC2 inhibitors for cancer therapy. In line with this goal, we propose to develop a pipeline for the discovery, characterization, and optimization of a novel class of PRC2 inhibitors. Our approach, which relies on targeting the RNA-binding site of PRC2 rather than its active site, represents a significant departure from the status quo, and is expected to overcome many of the limitations associated with current inhibitory strategies. Thus, if successful, this work will signify a major advance for treating cancers that are dependent on PRC2.

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