An Allosteric PRC2 Inhibitor Targeting EED Suppresses Tumor Progression by Modulating the Immune Response.

Aberrant activity of polycomb repressive complex 2 (PRC2) is involved in a wide range of human cancer progression. The WD40 repeat-containing protein EED is a core component of PRC2 and enhances PRC2 activity through interaction with H3K27me3. In this study, we report the discovery of a class of pyrimidone compounds, represented by BR-001, as potent allosteric inhibitors of PRC2. X-ray co-crystallography showed that BR-001 directly binds EED in the H3K27me3-binding pocket. BR-001 displayed antitumor potency in vitro and in vivo. In Karpas422 and Pfeiffer xenograft mouse models, twice daily oral dosing with BR-001 resulted in robust antitumor activity. BR-001 was also efficacious in syngeneic CT26 colon tumor-bearing mice; oral dosing of 30 mg/kg of BR-001 led to 59.3% tumor growth suppression and increased frequency of effector CD8+ T-cell infiltrates in tumors. Pharmacodynamic analysis revealed that CXCL10 was highly upregulated, suggesting that CXCL10 triggers the trafficking of CD8+ T cells toward tumor sites. Our results demonstrate for the first time that inhibition of EED modulates the tumor immune microenvironment to induce regression of colon tumors and therefore has the potential to be used in combination with immune-oncology therapy. SIGNIFICANCE: BR-001, a potent inhibitor of the EED subunit of the PRC2 complex, suppresses tumor progression by modulating the tumor microenvironment. ©2019 American Association for Cancer Research.