EED226 and A-395 bind to the H3K27me3 binding pocket of EED to allosterically inhibit PRC2.

  • Major finding: EED226 and A-395 bind to the H3K27me3 binding pocket of EED to allosterically inhibit PRC2.

  • Concept: Allosteric PRC2 inhibitors reduce DLBCL xenograft growth to a similar extent as EZH2 inhibitors.

  • Impact: Allosteric PRC2 inhibitors may be effective against tumors resistant to EZH2 inhibitors.

The polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 (H3K27me3) to promote gene silencing, and PRC2 dysregulation is commonly observed in multiple tumor types. PRC2 is comprised of three core subunits, the catalytic subunit EZH2, the H3K27me3-binding and scaffolding subunit EED, and SUZ12. Several small-molecule PRC2 inhibitors have been developed and are under investigation in clinical trials, but all are structurally similar and target the catalytic SET domain of EZH2. However, H3K27me3 recognition by EED is also essential for PRC2 activity, suggesting the possibility of developing allosteric inhibitors. Indeed, in related studies, Qi and colleagues and He and colleagues identified two compounds, EED226 and A-395, respectively, that bind directly to the H3K27me3 binding pocket of EED to allosterically inhibit PRC2. Crystal structures of each compound bound to the WD-40 domain of EED showed that EED226 and A-395 bind to the H3K27me3 binding pocket, and binding of the inhibitors induces a substantial conformational change in the EED binding pocket. Both EED226 and A-395 induced a selective global reduction in H3K27me3 levels in cancer cell lines. In vivo, A-395 and EED226 inhibited the growth of diffuse large B-cell lymphoma (DLBCL) xenografts and reduced H3K27me3 levels to a similar extent as an EZH2 inhibitor. Moreover, DLBCL cell lines that had acquired mutations rendering them resistant to EZH2 inhibitors remained sensitive to EED226 and A-395, indicating that allosteric PRC2 inhibitors may be effective in tumors that have developed resistance to EZH2 inhibition. Collectively, these findings indicate that inhibitors of the H3K27me3–EED interaction allosterically target PRC2 and are active against cells resistant to catalytic EZH2 inhibitors. Thus, these inhibitors warrant further investigation to overcome EZH2 inhibitor resistance and possibly in combination with EZH2 inhibitors to prevent resistance to either inhibitor.

Qi W, Zhao K, Gu J, Huang Y, Wang Y, Zhang H, et al. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat Chem Biol 2017 Jan 30 [Epub ahead of print].

He Y, Selvaraju S, Curtin ML, Jakob CG, Zhu H, Comess KM, et al. The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat Chem Biol 2017 Jan 30 [Epub ahead of print].