Background:

CRA-024781 is a novel HDAC inhibitor targeting HDAC1, HDAC2, HADC3, HADC6, HADC8, HADC10 with IC50 value of 7 nM(Ki), 19 nM(Ki), 8.2 nM(Ki), 17 nM(Ki), 280 nM(Ki), 24 nM(Ki), respectively [1].

Histone deacetylases (HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly.

CRA-024781 exhibits potent antitumor activity against ten human tumor cell lines with GI50 ranging from 0.15 μM to 3.09 μM. CRA-024781 also has an antiproliferative effect on HUVEC endothelial cells with GI50 of 0.43 μM. CRA-024781 treatment causes dose-dependent accumulation of both acetylated histones and acetylated tubulin in HCT116 or DLD-1 cells suggesting that HDAC enzymes are inhibited in these cells. CRA-024781 also induces the expression of p21 (a protein playing a role in the antitumor effect) and leads to PARP cleavage and accumulation of the γH2AX, which indicate apoptosis [1].

Treatment with CRA-024781 at 200 mg/kg once daily every other day significantly inhibits the growth of HCT116 and DLD-1 xenografts in mice by 69% and 59%, respectively. In the HCT116 model, treatment with CRA-024781 at 20 mg/kg, 40 mg/kg, 80 mg/kg, or 160 mg/kg (q.d. × 4 per week) causes inhibition of tumor growth by 48%, 57%, 82.2%, or 80.0%, respectively [1].

Reference:
[1].  Buggy JJ, Cao ZA, Bass KE, et al. CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo. Mol Cancer Ther, 2006, 5(5): 1309-1317.
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