CRA-026440 is a potent, broad-spectrum HDAC inhibitor (Kis: 4, 14, 11, 15, 7, and 20 nM for HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10).

Treatment of cultured tumor cell lines grown in vitro with CRA-026440 results in the accumulation of acetylated histone and acetylated tubulin, leading to an inhibition of tumor cell growth and the induction of apoptosis. Antitumor activity is observed in all 10 tumor cell lines tested, with GI50 values ranging from 0.12 to 9.95 μM. In addition, CRA-026440 has an antiproliferative effect on HUVEC endothelial cells (GI50: 1.41 μM).

CRA-026440 parenterally given to mice harboring HCT116 or U937 human tumor xenografts results in a statistically significant reduction in tumor growth. CRA-026440 is delivered i.v. to mice, and plasma concentrations are monitored over time. The clearance is calculated to be 38 mL/min/kg; the volume of distribution in the central compartment is 67 mL/kg. The steady-state volume of distribution is 454 mL/kg. The predominant plasma half-life is 7 minutes (44% of the area under the curve); and the mean residence time is 12 minutes. CRA-026440 at 25 and 50 mg/kg given qdx3 per week significantly inhibits tumor growth at 40% (P<0.01) and 58% (P<0.01), respectively. The combination of Avastin at 25 mg/kg once a week and CRA-026440 at 25 and 50 mg/kg for three consecutive days per week lead to more profound tumor growth inhibition of 84% (P< 0.01) and 85% (P<0.01), respectively. Compared with Avastin alone, the combination yields a marginally better result (P<0.1). The combination of Avastin and CRA-026440 at 50 mg/kg is significantly better than CRA-026440 alone at 50 mg/kg (P<0.05). Both combination treatments are well tolerated with maximal weight loss of<3%.

847460-34-8

C23H24N4O4

420.46

(< 1 mg/ml refers to the product slightly soluble or insoluble )
Powder: -20°C for 3 years
In solvent: -80°C for 2 years