EZH2-EED Inhibitors

EZH2 is the histone methyltransferase subunit of the Polycomb Repressor complex 2 (PRC2) which is an important epigenetic regulator of cell differentiation and gene expression. PRC2 is a multi-protein complex comprised of EZH2, EED and SUZ12 as critical factors.

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The founders of OncoFusion first described in publication the role of EZH2 and PRC2 in aggressive forms of prostate and breast cancer, and it has since been found to be over-expressed in a wide range of epithelial tumors including small-cell lung cancer. While EZH2 has not been described as part of a gene fusion, SUZ12 (which is a critical component of PRC2) has been described as a recurrent gene fusion in endometrial stromal tissues. Furthermore, activating mutations of EZH2 have been found in B-cell lymphomas.

While the conventional approach to develop inhibitors against EZH2 targets the enzymatic SET domain of the molecule, unpublished studies suggest that these inhibitors may have poor activity against EZH2 over-expressing tumors.

Thus, OncoFusion has approached this problem by exploring novel mechanism of action (MOA) inhibitors that disrupt protein-protein interactions within the PRC2 complex—specifically inhibiting the EZH2-EED protein-protein interface. The best lead compounds have low nanomolar binding affinities and exhibit potency in tumor cell lines.

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