title: 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.affiliation: CCU Pediatric Oncology (G340), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wegener
authors.forename: Hedwig E
authors.initials: HE
authors.lastname: Deubzer
authors.forename: Ina
authors.initials: I
authors.lastname: Oehme
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.forename: Christian
authors.initials: C
authors.lastname: Hildmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Schwienhorst
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt