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  • Oehme, Ina  (45)
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  • 1
    Language: English
    In: Journal of medicinal chemistry, 25 February 2016, Vol.59(4), pp.1545-55
    Description: Histone deacetylase 6 (HDAC6) catalyzes the removal of an acetyl group from lysine residues of several non-histone proteins. Here we report the preparation of thiazole-, oxazole-, and oxadiazole-containing biarylhydroxamic acids by a short synthetic procedure. We identified them as selective HDAC6 inhibitors by investigating the inhibition of recombinant HDAC enzymes and the protein acetylation in cells by Western blotting (tubulin vs histone acetylation). The most active compounds exhibited nanomolar potency and high selectivity for HDAC6. For example, an oxazole hydroxamate inhibits HDAC6 with an IC50 of 59 nM and has a selectivity index of 〉200 against HDAC1 and HDAC8. This is the first report showing that the nature of a heterocycle directly connected to a zinc binding group (ZBG) can be used to modulate subtype selectivity and potency for HDAC6 inhibitors to such an extent. We rationalize the high potency and selectivity of the oxazoles by molecular modeling and docking.
    Keywords: Histone Deacetylase Inhibitors -- Chemistry ; Histone Deacetylases -- Metabolism ; Hydroxamic Acids -- Chemistry ; Oxazoles -- Chemistry
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 2
    Language: English
    In: International Journal of Cancer, 01 May 2013, Vol.132(9), pp.2200-2208
    Description: Inhibition of histone deacetylase (HDAC) activity as stand‐alone or combination therapy represents a promising therapeutic approach in oncology. The pan‐ or class I HDAC inhibitors (HDACi) currently approved or in clinical studies for oncology give rise to dose‐limiting toxicities, presumably because of the inhibition of several HDACs. This could potentially be overcome by selective blockade of single HDAC family members. Here we report that HDAC11, the most recently identified zinc‐dependent HDAC, is overexpressed in several carcinomas as compared to corresponding healthy tissues. HDAC11 depletion is sufficient to cause cell death and to inhibit metabolic activity in HCT‐116 colon, PC‐3 prostate, MCF‐7 breast and SK‐OV‐3 ovarian cancer cell lines. The antitumoral effect induced can be mimicked by enforced expression of a catalytically impaired HDAC11 variant, suggesting that inhibition of the enzymatic activity of HDAC11 by small molecules could trigger the desired phenotypic changes. HDAC11 depletion in normal cells causes no changes in metabolic activity and viability, strongly suggesting that tumor‐selective effects can be achieved. Altogether, our data show that HDAC11 plays a critical role in cancer cell survival and may represent a novel drug target in oncology. What's new? Histone deacetylase (HDAC) enzymes influence the regulation of numerous cellular processes, and their inhibition by small molecules has been shown to provide benefits against multiple cancer types. Here, HDAC11, a recently identified member of the HDAC family, was found to play an important role in the control of proliferation and survival pathways in several carcinoma cell lines. The high incidence of the tumors represented suggests that HDAC11 could be a valuable drug target in oncology.
    Keywords: Chromatin Modulation ; Targeted Therapy ; Histone Deacetylase ; Colon Cancer ; Prostate Cancer
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 09 July 2013, Vol.110(28), pp.E2592-601
    Description: Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome.
    Keywords: Hdac Inhibitor ; Childhood Tumors ; Drug Resistance ; Autophagy -- Physiology ; Cell Survival -- Physiology ; Histone Deacetylases -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
  • 5
    Language: English
    In: Journal of medicinal chemistry, 28 December 2017, Vol.60(24), pp.10188-10204
    Description: Histone deacetylases (HDACs) are important modulators of epigenetic gene regulation and additionally control the activity of non-histone protein substrates. While for HDACs 1-3 and 6 many potent selective inhibitors have been obtained, for other subtypes much less is known on selective inhibitors and the consequences of their inhibition. The present report describes the development of substituted benzhydroxamic acids as potent and selective HDAC8 inhibitors. Docking studies using available crystal structures have been used for structure-based optimization of this series of compounds. Within this study, we have investigated the role of HDAC8 in the proliferation of cancer cells and optimized hits for potency and selectivity, both in vitro and in cell culture. The combination of structure-based design, synthesis, and in vitro screening to cellular testing resulted in potent and selective HDAC8 inhibitors that showed anti-neuroblastoma activity in cellular testing.
    Keywords: Antineoplastic Agents–Chemistry ; Biomarkers, Tumor–Pharmacology ; Cell Line, Tumor–Genetics ; Drug Design–Drug Effects ; Drug Screening Assays, Antitumor–Chemistry ; Gene Expression Regulation, Neoplastic–Pharmacology ; Hek293 Cells–Chemistry ; Histone Deacetylase Inhibitors–Metabolism ; Histone Deacetylases–Chemistry ; Humans–Drug Therapy ; Hydroxamic Acids–Genetics ; Molecular Docking Simulation–Pathology ; Neuroblastoma–Antagonists & Inhibitors ; Repressor Proteins–Chemistry ; Structure-Activity Relationship–Metabolism ; Antineoplastic Agents ; Biomarkers, Tumor ; Histone Deacetylase Inhibitors ; Hydroxamic Acids ; Repressor Proteins ; Hdac8 Protein, Human ; Histone Deacetylases ; Benzohydroxamic Acid;
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 6
    Language: English
    In: NUCLEIC ACIDS RESEARCH, 2013
    Description: MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function.
    Keywords: Biology And Life Sciences ; Cell-Line ; Down-Regulation ; Microrna Expression ; Colorectal-Cancer ; Apoptosis ; Microarray ; Carcinoma ; Family ; Differentiation ; Histone Deacetylase Inhibitors
    ISSN: 0305-1048
    E-ISSN: 13624962
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  • 7
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 June 2010, Vol.16(12), pp.3240-52
    Description: Medulloblastomas are the most common malignant brain tumors in childhood. Survivors suffer from high morbidity because of therapy-related side effects. Thus, therapies targeting tumors in a specific manner with small molecules such as histone deacetylase (HDAC) inhibitors are urgently warranted. This study investigated the expression levels of individual human HDAC family members in primary medulloblastoma samples, their potential as risk stratification markers, and their roles in tumor cell growth. Gene expression arrays were used to screen for HDAC1 through HDAC11. Using quantitative real time reverse transcriptase-PCR and immunohistochemistry, we studied the expression of HDAC5 and HDAC9 in primary medulloblastoma samples. In addition, we conducted functional studies using siRNA-mediated knockdown of HDAC5 and HDAC9 in medulloblastoma cells. HDAC5 and HDAC9 showed the highest expression in prognostically poor subgroups. This finding was validated in an independent set of medulloblastoma samples. High HDAC5 and HDAC9 expression was significantly associated with poor overall survival, with high HDAC5 and HDAC9 expression posing an independent risk factor. Immunohistochemistry revealed a strong expression of HDAC5 and HDAC9 proteins in most of all primary medulloblastomas investigated. siRNA-mediated knockdown of HDAC5 or HDAC9 in medulloblastoma cells resulted in decreased cell growth and cell viability. HDAC5 and HDAC9 are significantly upregulated in high-risk medulloblastoma in comparison with low-risk medulloblastoma, and their expression is associated with poor survival. Thus, HDAC5 and HDAC9 may be valuable markers for risk stratification. Because our functional studies point toward a role in medulloblastoma cell growth, HDAC5 and HDAC9 may potentially be novel drug targets.
    Keywords: Biomarkers, Tumor -- Metabolism ; Brain Neoplasms -- Metabolism ; Histone Deacetylases -- Metabolism ; Medulloblastoma -- Metabolism ; Repressor Proteins -- Metabolism
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 8
    Language: English
    In: Cells, 01 April 2015, Vol.4(2), pp.135-168
    Description: The exploitation of autophagy by some cancer entities to support survival and dodge death has been well-described. Though its role as a constitutive process is important in normal, healthy cells, in the milieu of malignantly transformed and highly proliferative cells, autophagy is critical for escaping metabolic and genetic stressors. In recent years, the importance of histone deacetylases (HDACs) in cancer biology has been heavily investigated, and the enzyme family has been shown to play a role in autophagy, too. HDAC inhibitors (HDACi) are being integrated into cancer therapy and clinical trials are ongoing. The effect of HDACi on autophagy and, conversely, the effect of autophagy on HDACi efficacy are currently under investigation. With the development of HDACi that are able to selectively target individual HDAC isozymes, there is great potential for specific therapy that has more well-defined effects on cancer biology and also minimizes toxicity. Here, the role of autophagy in the context of cancer and the interplay of this process with HDACs will be summarized. Identification of key HDAC isozymes involved in autophagy and the ability to target specific isozymes yields the potential to cripple and ultimately eliminate malignant cells depending on autophagy as a survival mechanism.
    Keywords: Histone Deacetylase Inhibitor ; Cancer ; Hdac6 ; Hdac10 ; Autophagic Flux ; Targeted Therapy ; Biology
    E-ISSN: 2073-4409
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  • 9
    Language: English
    In: Autophagy, 05 December 2013, Vol.9(12), pp.2163-2165
    Description: Neuroblastoma is the most common extracranial solid tumor in childhood. Despite intense multimodal therapy and many improvements through basic scientific and clinical research, the successful response of advanced-stage patients to chemotherapy remains poor. Autophagy is a cytoprotective mechanism...
    Keywords: Hdac10 ; Neuroblastoma ; Drug Resistance ; Hdac-Inhibitor ; Lysosome ; Macroautophagy ; Biology
    ISSN: 1554-8627
    E-ISSN: 1554-8635
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  • 10
    Language: English
    In: Cancer Letters, 2009, Vol.277(1), pp.8-21
    Description: Histone deacetylases comprise a family of 18 genes, which are grouped into classes I–IV based on their homology to their respective yeast orthologues. Classes I, II, and IV consist of 11 family members, which are referred to as “classical” HDACs, whereas the 7 class III members are called sirtuins. Classical HDACs are a promising novel class of anti-cancer drug targets. First HDAC inhibitors have been evaluated in clinical trials and show activity against several cancer diseases. However, these compounds act unselectively against several or all 11 HDAC family members. As a consequence, clinical phase I trials document a wide range of side effects. Therefore, the current challenge in the field is to define the cancer relevant HDAC family member(s) in a given tumor type and to design selective inhibitors, which target cancer cells but leave out normal cells. Knockout of single HDAC family members in mice produces a variety of phenotypes ranging from early embryonic death to viable animals with only discrete alterations, indicating that potential side effects of HDAC inhibitors depend on the selectivity of the compounds. Recently, several studies have shown that certain HDAC family members are aberrantly expressed in several tumors and have non-redundant function in controlling hallmarks of cancer cells. The aim of this review is to discuss individual HDAC family members as drug targets in cancer taking into consideration their function under physiological conditions and their oncogenic potential in malignant disease.
    Keywords: Histone Deacetylase ; Hdac ; Hdac Inhibitor ; Cancer ; Development ; Therapy ; Medicine
    ISSN: 0304-3835
    E-ISSN: 1872-7980
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