HKI 46F08, a novel potent histone deacetylase inhibitor, exhibits antitumoral activity against embryonic childhood cancer cells.

Abstract

Embryonic childhood cancer such as neuroblastoma and medulloblastoma are still a therapeutic challenge requiring novel treatment approaches. Here, we investigated the antitumoral effects of HKI 46F08, a novel trifluoromethyl ketone histone deacetylase (HDAC) inhibitor with a nonhydroxamic acid type structure. HKI 46F08 inhibits in-vitro HDAC activity in cell-free assays with a half maximal inhibitory concentration of 0.6 micromol/l and intracellular HDAC activity with a half maximal inhibitory concentration of 1.8 micromol/l. The compound reduces viability of both cultured neuroblastoma and medulloblastoma cells with an EC50 of 0.1-4 micromol/l. HKI 46F08 efficiently arrests tumor cell proliferation, represses clonogenic growth and induces differentiation and apoptosis in both MYCN-amplified and nonamplified neuroblastoma cells. In summary, we identified HKI 48F08 as a structural novel, potent HDAC inhibitor with strong antitumoral activity against embryonic childhood cancer cells in the low micromolar range.

• Authors: Dennis Wegener, Hedwig E Deubzer, Ina Oehme, Till Milde, Christian Hildmann, Andreas Schwienhorst, Olaf Witt
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 19 Issue 9 Pg. 849-57 (Oct 2008) ISSN: 0959-4973 [Print] England
• PMID: 18765999 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzimidazoles
• Enzyme Inhibitors
• HKI 46F08
• Histone Deacetylase Inhibitors

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzimidazoles (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (pharmacology)
• Histone Deacetylase Inhibitors
• Humans
• Medulloblastoma (drug therapy)
• Neuroblastoma (drug therapy)
• Rats