IC50: 10 nM

CPI-455 is a KDM5 inhibitor.

The KDM5 family of histone demethylases catalyzes the demethylation of histone H3 on lysine 4 (H3K4) and is required for the survival of drug-tolerant persister cancer cells (DTPs).

In vitro: Previous study found that CPI-455 could potently inhibit the fulllength KDM5A in enzymatic assays with a half-maximal inhibitory concentration of 10 ± 1 nM. CPI-455 inhibited KDM5A, KDM5B and KDM5C to similar levels but showed significantly weaker potency toward KDM4C and KDM7B (~200- and 770-fold, respectively) and no detectable inhibition of KDM2B, KDM3B or KDM6A. Moreover, it was found that the CPI-455-mediated KDM5 inhibition led to a dose-dependent increase in global H3K4me3 in HeLa cells, and the removal of CPI-455 resulted in a rapid reversal of H3K4me3 increases in HeLa cells. Moreover, CPI-455 could delay the appearance of heavy H3K4me3, which was consistent with the role for KDM5 enzymes in H3K4me3 turnover, however, the turnover of H3K4me2 was only marginally altered. As expected, CPI-455 could affect the turnover of H3K4 monomethylation [1].

In vivo: So far, there is no animal in vivo data reported.

Clinical trial: Up to now, CPI-455 is still in the preclinical development stage.

Reference:
[1] Vinogradova M, et al.? An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. Nat Chem Biol. 2016 Jul;12(7):531-8.