CPI-360

The molelcule has excellent selectivity for H3K27Me3 (EZH2) over H3K27Me1 (EZH1) in cells, so this appears to be an excellent orthogonal molecule to existing probes.

CPI-360 appears to be a potent and selective inhibitor of EZH2 in both biochemical and cellular assays, with selectivity over EZH1 and several other methytransferases. As such, it offers a useful tool to complement compounds such as GSK343. The compound appears to show in vivo efficacy in xenograft models, but at very high dosing (200 mg/kg compared with a cellular potency of 50 nM), suggesting potential deficiencies in the PK profile. Disappointingly, no PK data are given to allow assessment of this aspect, and as such, any use in vivo should proceed with caution, ideally only after gaining an understanding of the full PK and dose/exposure relationships.

This probe has good selectivity and cell activity. However, the discoverers noted that in mice even at the very high subcutaneous dose of 200 mg/kg the "inadequate pharmacological properties of CPI-360 did not allow for complete target coverage." This appears to be in part due to poor microsomal stability, which is given as 166/138/106/110 μl/min/mg (for m/r/d/h) in Supplementary Figure S5. The closely related compound CPI-169 is more stable, shows better activity in a xenograft model, and appears to have a similarly favorable selectivity and potency profile, suggesting that CPI-169 may be a superior probe. The in vivo dose may need to be adjusted for longer in vivo experiments