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Identification of Novel Small-Molecule Histone Deacetylase Inhibitors By Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorogenic assay Dennis Wegener, Christian Hildmann, Daniel Riester, Andreas Schober, Franz-Josef Meyer-Almes, Hedwig Deubzer, Ina Oehme, Olaf Witt, Siegmund Lang, Martina Jaensch, et al. To cite this version: Dennis Wegener, Christian Hildmann, Daniel Riester, Andreas Schober, Franz-Josef Meyer-Almes, et al.. Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorogenic assay. Biochemical Journal, Portland Press, 2008, 413 (1), pp.143-150. 10.1042/BJ20080536. hal-00478995 HAL Id: hal-00478995 https://hal.archives-ouvertes.fr/hal-00478995 Submitted on 30 Apr 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Biochemical Journal Immediate Publication. Published on 25 Mar 2008 as manuscript BJ20080536 Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorogenic assay Dennis Wegener1,2,3, Christian Hildmann1,2*, Daniel Riester1, Andreas Schober2, Franz- Josef Meyer-Almes4, Hedwig E. Deubzer3, Ina Oehme3, Olaf Witt3, Siegmund Lang5, Martina Jaensch6, Vadim Makarov7, Corinna Lange8, Benedikt Busse9 and Andreas Schwienhorst1 1 Department of Molecular Genetics and Preparative Molecular Biology, Institute for Microbiology und Genetics, Grisebachstr. 8, 37077 Goettingen, Germany 2 Institute for Micro- and Nanotechnologies, Technical University of Ilmenau, Gustaf-Kirchhoff-Straße 7, 98693 Ilmenau, Germany 3 CCU Pediatric Oncology G340, German Cancer Research Center (DKFZ) Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany 4 Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Schnittspahnstr. 12, 64287 Darmstadt, Germany 5 TU Braunschweig, Institut für Biochemie und Biotechnologie, Spielmannstr. 7, 38106 Braunschweig, Germany 6 AnalytiCon Discovery GmbH, Hermannswerder Haus 17, 14473 Potsdam, Germany 7 State Research Center for Antibiotics, 3f, Nagatinsksaya str., Moscow 117105 Russia 8 Leibniz-Institut für Naturstoffforschung und Infektionsbiologie,-Hans-Knöll Institut, Beutenbergstr. 11a, 07745 Jena, Germany 9 zell-kontakt GmbH, Industriestrasse 3, 37176 Noerten-Hardenberg, Germany SHORT TITLE: HDAH inhibitor screening _______________________________________________________________ *To whom correspondence should be addressed: Christian Hildmann Technical University Ilmenau Institute for Micro- and Nanotechnologies (ZMN) Gustav-Kirchhoff-Str. 7 98693 Ilmenau THIS IS NOT THE FINAL VERSION - see doi:10.1042/BJ20080536 Germany Phone: 49-3677-693410; fax: 49-3677-693455; Email: [email protected] Stage 2(a) POST-PRINT 1 Licenced copy. Copying is not permitted, except with prior permission and as allowed by law. © 2008 The Authors Journal compilation © 2008 Biochemical Society Biochemical Journal Immediate Publication. Published on 25 Mar 2008 as manuscript BJ20080536 The abbreviations used: MCA 7-amino-4-methylcoumarin DMSO dimethylsulfoxide FRET fluorescence resonance energy transfer HDAC histone deacetylase HDAH histone deacetylase-like amidohydrolase (from strain FB188) IC50 Inhibitor concentration at 50 % inhibition MCA 4-methylcoumarin-7-amide PAGE polyacryl amide gel electrophoresis PBS phosphate buffered saline PEG polyethylene glycol RT room temperature SAHA suberoylanilide hydroxamic acid TBS Tris-buffered saline Tos Tosyl TSA trichostatin A VPA valproic acid KEY WORDS: FB188 HDAH, high-throughput screening, trifluoromethylketone, pyran-4- one, p-benzochinone, chromone ABSTRACT Histone deacetylases (HDACs) are considered to be among the most important enzymes regulating 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 tumor-suppressor genes leading to an aberrant recruitment of HDAC activity, which results in changes of gene expression, impaired differentiation and excessive proliferation of tumor cells. Therefore, HDAC-inhibitors are efficient anti-proliferative agents in both in vitro and in vivo preclinical models of cancer making them promising anti-cancer therapeutics. Here, we present the results of a medium-throughput screening program aiming at the identification of novel HDAC-inhibitors using histone deacetylase-like amidohydrolase from strain FB188 (FB188 HDAH) as model enzyme. Within a library of 3719 compounds, THIS IS NOT THE FINAL VERSION - see doi:10.1042/BJ20080536 several new classes of HDAC-inhibitors 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 tumor 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. INTRODUCTION Histone deacetylases (HDACs) are important enzymes in the regulation of gene expression in eukaryotic cells [1]. Together with histone acetyltransferases (HATs) HDACs maintain the delicate equilibrium between acetylated and deacetylated ε-amino groups of lysines in the aminoStage terminal parts of histone 2(a) proteins. In general,POST-PRINT increased levels of histone acetylation are associated with increased transcriptional activity, whereas decreased levels of acetylation are 2 Licenced copy. Copying is not permitted, except with prior permission and as allowed by law. © 2008 The Authors Journal compilation © 2008 Biochemical Society Biochemical Journal Immediate Publication. Published on 25 Mar 2008 as manuscript BJ20080536 associated with repression of gene expression [2]. Although histone deacetylation appears to have a fundamental role in regulating gene expression, HDAC inhibitors seem to directly affect transcription of only a relatively small number of genes [3, 4]. Most of the genes regulated by HDAC inhibitors participate in the control of cell growth and survival, providing a mechanistic explanation for the anticancer properties of these inhibitors. Particularly, activation of differentiation programs, inhibition of the cell cycle and induction of apoptosis are key antitumor activities that make HDAC inhibitors promising anticancer agents. Several synthetic compounds and natural products have been reported to inhibit HDACs (reviewed in:[5-7]. Furthermore, a small number of drug candidates are currently in phase I – III clinical trials (reviewed in: [8] with the first drug, vorinostat (Zolinza, Merck & Co., Inc.) recently approved by the FDA. However, many currently available HDAC inhibitors are disadvantageous e.g. in regard of their limited metabolic stability [9, 10] or their cross- reactivity against other enzymes such as esterases [11]. Thus, there is still a need for new HDAC inhibitors belonging to yet unexplored structural classes of compounds. Here, we report the identification of novel small-molecule HDAC inhibitors through medium- throughput screening of a compound library using a bacterial histone deacetylase-like amidohydrolase (HDAH; [12-14]) as a model system. Several of the compounds specifically inhibit the bacterial enzyme. Other compounds proved to be pan-inhibitors that also inhibit eukaryotic HDACs and induce hyperacetylation in a neuroblastoma cell line (SHEP) and bladder carcinoma cells (T24). The novel inhibitor structures provide new lead structures for further development of improved anticancer drugs. EXPERIMENTAL Reagents FB188-HDAH was expressed in E. coli and purified by affinity chromatography (Zn2+- IMAC) as described [12]. The enzyme was stable for weeks as 150 µg/ml solution in 10 mM potassium phosphate, pH 8.0 at 4°C. Rat liver HDAC was purchased from Merk Biosciences (Bad Soden, Germany), whereas human HDAC8 was expressed in E. coli and purified as described [15]. Trypsin from porcine pancreas (Type IX-S, 13,000–20,000 BAEE units/mg) was purchased from Sigma (Taufkirchen, Germany) and after solvation in trypsin buffer (50 mM Tris-HCl, pH 8.5, 100 mM NaCl, 0.1% PEG8000) to a solution of 10 mg/ml was stable for several days at 4 °C. Boc-Lys(Ac)-MCA (Bachem, Weil am Rhein, Germany) and Tos- GPR-MCA (Sigma, Taufkirchen, Germany) were dissolved to 30 mM in DMSO. Tos- GPK(Ac)-MCA was synthesized as described [16]. Sodium valproate (Sigma, Taufkirchen, Germany) was dissolved to 1 M in phosphate-buffered saline (PBS) and stored at -20 °C. Apart from RPMI 1640 medium and trypsin/EDTA (Cambrex, Nottingham, UK), all cell culture reagents were purchased from Sigma (Taufkirchen Germany). THIS IS NOT THE FINAL VERSION - see doi:10.1042/BJ20080536 Library Screening The compound collection was obtained from the Hans-Knöll-Institute (HKI, Jena) as solutions of approximately 10 µg/ml and stored at -80 °C. The thawed substances were diluted 1:25 in assay
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