EED inhibition suppresses cancers by modulating the immune response

Cancer Research
Hongping DongBin Zou

Abstract

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 anti-tumor potency in vitro and in vivo. In Karpas422 and Pfeiffer xenograft mouse models, twice-daily oral dosing with BR-001 resulted in robust anti-tumor 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 cell towards 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...Continue Reading

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Citations

Dec 8, 2020·Endocrinology·Anca M FarcasJason S Carroll
Oct 27, 2020·Expert Opinion on Therapeutic Patents·Milly DockerillDaniel H O' Donovan
Apr 4, 2021·International Journal of Molecular Sciences·Sarah BruntyNalini Santanam
Jun 1, 2021·Signal Transduction and Targeted Therapy·Lei ZhongShengyong Yang
Jun 3, 2021·Journal of Medicinal Chemistry·Daohai DuCheng Luo
Aug 17, 2020·Cell Chemical Biology·Dhanusha A Nalawansha, Craig M Crews
Dec 8, 2020·Journal of Medicinal Chemistry·M Cynthia MartinGary E Schiltz
Sep 3, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Zehui TanXin Zhai

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