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  • 1
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; DRUG ; DIFFERENTIATION ; INDUCTION ; ACID ; NERVOUS-SYSTEM ; ASSAY ; CANCER-CELLS ; HISTONE DEACETYLASE ; histone deacetylase inhibitor ; p21(waf1) ; neuroblastoma ; INVITRO ; LEUKEMIA-CELLS ; ONCOLOGY ; CHILDHOOD ; RE ; medulloblastoma ; cell proliferation ; ASSAYS ; pharmacology ; USA ; anticancer drug ; childhood cancer ; HELMINTHOSPORIUM-CARBONUM (HC)-TOXIN ; HKI46F08
    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 mu mol/l and intracellular HDAC activity with a half maximal inhibitory concentration of 1.8 mu mol/l. The compound reduces viability of both cultured neuroblastoma and medulloblastoma cells with an EC50 of 0.1-4 mu mol/l. HKI 461708 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
    Type of Publication: Journal article published
    PubMed ID: 18765999
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; proliferation ; AGENTS ; carcinoma ; CELL ; Germany ; IN-VIVO ; MODEL ; MODELS ; VITRO ; VIVO ; screening ; ENZYMES ; GENE ; GENE-EXPRESSION ; GENES ; METABOLISM ; DIFFERENTIATION ; INDUCTION ; BIOLOGY ; MOLECULAR-BIOLOGY ; IDENTIFICATION ; gene expression ; TRANSCRIPTIONAL ACTIVITY ; ASSAY ; CARCINOMA CELLS ; NUMBER ; EFFICIENT ; acetylation ; CARCINOMA-CELLS ; ONCOGENE ; PHENOTYPE ; RECRUITMENT ; specificity ; HISTONE DEACETYLASE ; histone deacetylase inhibitor ; REPRESSION ; neuroblastoma ; INHIBITORS ; AGENT ; molecular biology ; molecular ; INCREASE ; LEVEL ; ENZYME ; HISTONE DEACETYLASE INHIBITORS ; HISTONE ACETYLATION ; H4 ; ENGLAND ; amidohydrolase ; STRAIN ; SMALL-MOLECULE ; ACTINOMYCIN-D ; amidohydrolase (HDAH) ; chromone ; histone deacetylase-like ; KETONE INHIBITORS ; LEUKEMIA-CELL LINE ; medium-throughput screening ; p-benzoquinone ; pyran-4-one ; SOPHOROSE LIPIDS ; trifluoromethylketone
    Abstract: HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells. In general, increased levels of histone acetylation are associated with increased transcriptional activity, whereas decreased levels are linked to repression of gene,expression. HDACs associate with a number of cellular oncogenes and tumour-suppressor genes, leading to an aberrant recruitment of HDAC activity, which results in changes of gene expression, impaired differentiation and excessive proliferation of tumour cells. Therefore HDAC inhibitors are efficient anti-proliferative agents in both in vitro and in vivo pre-clinical models of cancer, making them promising anticancer therapeutics. In the present paper, we present the results of a medium-throughput screening programme aiming at the identification of novel HDAC inhibitors using HDAH (HDAC-like amidohydrolase) from Bordetella or Alcaligenes strain FB188 as a model enzyme. Within a library of 3719 compounds, several new classes of HDAC inhibitor were identified. Among these hit compounds, there were also potent inhibitors of eukaryotic HDACs, as demonstrated by an increase in histone H4 acetylation, accompanied by a decrease in tumour cell metabolism in both SHEP neuroblastoma and T24 bladder carcinoma cells. In conclusion, screening of a compound library using FB188 HDAH as model enzyme identified several promising new lead structures for further development
    Type of Publication: Journal article published
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  • 3
    Keywords: CANCER ; CELLS ; EXPRESSION ; INHIBITOR ; CELL ; Germany ; human ; IN-VIVO ; THERAPY ; liver ; SITE ; ENZYMES ; GENE ; GENE-EXPRESSION ; PROTEIN ; DRUG ; MOLECULES ; MECHANISM ; BIOLOGY ; MOLECULAR-BIOLOGY ; SEQUENCE ; MOLECULE ; ACID ; TARGET ; gene expression ; DIFFERENCE ; MUTATION ; acetylation ; CRYSTAL-STRUCTURE ; MICROTUBULES ; specificity ; TARGETS ; HISTONE DEACETYLASE ; CANCER-THERAPY ; TRANSCRIPTIONAL REPRESSION ; SUBSTRATE-SPECIFICITY ; INHIBITORS ; molecular biology ; molecular ; RESIDUES ; THERAPIES ; cancer therapy ; DEACETYLASE ; SUBSTRATE ; LIPASE ; ENZYME ; ROLES ; BIOLOGICAL-ACTIVITY ; CANDIDATE ; ENGLAND ; comparison ; block ; CANDIDATES ; HISTONES ; bacterial ; amidohydrolase ; Bordetella/Alcaligenes ; DEACETYLATION ; esterase ; fluorogenic assay ; HUMAN HDAC8 ; SUBTILISIN BACILLUS-LENTUS
    Abstract: HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells acting through deacetylation of epsilon-acetyl-lysine residues within the N-terminal tail of core histones. In addition, both eukaryotic HDACs as well as their bacterial counterparts were reported to also act on non-histone targets. However, we are still far from a comprehensive understanding of the biological activities of this ancient class of enzymes. In the present paper, we studied in more detail the esterase activity of HDACs, focussing on the HDAH (histone deacetylase-like amidohydrolase) from Bordetella/Alcaligenes strain FB188. This enzyme was classified as a class 2 HDAC based on sequence comparison as well as functional data. Using chromogenic and fluorogenic ester substrates we show that HDACs such as FB188 HDAH indeed have esterase activity that is comparable with those of known esterases. Similar results were obtained for human HDAC1, 3 and 8. Standard HDAC inhibitors were able to block both activities with similar IC50 values. Interestingly, HDAC inhibitors such as suberoylanilide hydroxamic acid (SARA) also showed inhibitory activity against porcine liver esterase and Pseudomonas fluorescens lipase. The esterase and the amidohydrolase activity of FB188 HDAH both appear to have the same substrate specificity concerning the acyl moiety. Interestingly, a Y312F mutation in the active site of HDAH obstructed amidohydrolase activity but significantly improved esterase activity, indicating subtle differences in the mechanism of both catalytic activities. Our results suggest that, in principle, HDACs may have other biological roles besides acting as protein deacetylases. Furthermore, data on HDAC inhibitors affecting known esterases indicate that these molecules, which are currently among the most promising drug candidates in cancer therapy, may have a broader target profile requiring further exploration
    Type of Publication: Journal article published
    PubMed ID: 17037985
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  • 4
    Keywords: CANCER ; INHIBITOR ; Germany ; human ; INFORMATION ; SITE ; ENZYMES ; DRUG ; COMPLEX ; COMPLEXES ; BINDING ; BIOLOGY ; MOLECULAR-BIOLOGY ; ACID ; ACIDS ; TARGET ; DESIGN ; DIFFERENCE ; NUMBER ; DERIVATIVES ; CRYSTAL-STRUCTURE ; AMINO-ACIDS ; REVEALS ; TARGETS ; HISTONE DEACETYLASE ; INHIBITORS ; molecular biology ; molecular ; HOMOLOGY ; AMINO-ACID ; interaction ; DEACETYLASE ; development ; ENZYME ; methods ; ATOMS ; ENGLAND ; anticancer drug ; comparison ; ELASTASE ; bacterial ; HUMAN HDAC8
    Abstract: Histone deacetylases (HDACs) have emerged as attractive targets in anticancer drug development. To date, a number of HDAC inhibitors have been developed and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA). Not surprisingly, structural information that can greatly enhance the design of novel HDAC inhibitors is so far only available for hydroxamic acids in complex with HDAC or HDAC-like enzymes. Here, the first structure of an enzyme complex with a nonhydroxamate HDAC inhibitor is presented. The structure of the trifluoromethyl ketone inhibitor 9,9,9-trifluoro-8-oxo-N-phenylnonanamide in complex with bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) has been determined. HDAH reveals high sequential and functional homology to human class 2 HDACs and a high structural homology to human class 1 HDACs. Comparison with the structure of HDAH in complex with SAHA reveals that the two inhibitors superimpose well. However, significant differences in binding to the active site of HDAH were observed. In the presented structure the O atom of the trifluoromethyl ketone moiety is within binding distance of the Zn atom of the enzyme and the F atoms participate in interactions with the enzyme, thereby involving more amino acids in enzyme-inhibitor binding
    Type of Publication: Journal article published
    PubMed ID: 17401192
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  • 5
    Keywords: Germany ; CELL ; INHIBITOR ; CELLS ; NEUROBLASTOMA-CELLS ; screening ; neuroblastoma ; COMPOUND ; LIBRARIES
    Type of Publication: Meeting abstract published
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