overview
 

Histone deacetylases

Sirtuins

Histon acetyltransferases

Methyltransferases

References

 

 

 

Epigenetics - Inhibitors of histone modifying enzymes

   

Epigenetics means inheritable changes in the expression of proteins and hence the function of a cell WITHOUT alterations in the genetic code.

Such changes may be induced by DNA methylation and by modifications in histone proteins. Histones are basic proteins that are associated with DNA and their complex is termed chromatin. Enzymatic modifications in histones such as the reversible acetylation or methylation of the side chains of lysine residues contribute to gene regulation. They are involved in the pathogenesis of cancer but also other diseases and serve as a target for drug discovery. First inhibitors of epigenetic pathways have been approved for clinical use (e.g. histone deacetylase: Vorinostat (Zolinza™). Non-histone proteins undergo similar modifications and epigenetic drugs may also exert effects via these signal transduction pathways.

Our main research focus is on assay development and the synthesis of inhibitors of histone modifying enzymes. We focus on zinc dependent histone deacetylases (HDACs), NAD+ dependent histone deacetylases (sirtuins), histone acetyltransferases (HATs) and histone methyltransferases. Part of the biological data is obtained in collaborating laboratories. In the area of Molecular Modelling we collaborate with Prof. Dr. W. Sippl (University of Halle).

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Inhibitors of zinc dependent histone deacetylases (HDACs)

  • Synthesis of the first druglike HDAC inhibitors

  • Development of a small molecule HDAC substrates (MAL) and a HTS-HDAC-assays

  • Development of subtype selective (HDAC1 und HDAC6) HDAC substrates

  • Synthesis of HDAC6 selective inhibitors

  • Biological activities: Inhibition of proliferation, induction of differentiation, radiosensitization of cancer cells, globin expression

hdac

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Inhbitors of NAD+ dependent histone deacetylases (sirtuins)

  • Synthesis of subtype selective sirtuin inhibitors

  • Development of a small molecule sirtuin substrate (ZMAL) and a HTS sirtuin assays

  • Kinase inhibitors of new lead structures for sirtuin inhibitors (Focussed library screening)

  • Biological activities: Inhibition of proliferation, block of HIV transcription


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Inhibitors of histone acetyltransferases (HATs)

  • Lead structure based approach to new HAT inhibitors

  • Biological activities: Inhibition of proliferation


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Inhbitors of arginine methyltransferases (PRMTs)

  • First inhibitors by a rational approach (Virtual Screening)

  • First bisubstrate inhibitor of PRMTs

  • Development of HTS-Assays for cellular arginine and lysine methylation

  • Biological activities: Block of activation of hormone rezeptors

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Selected references from our group


Review articles

Chromatin modifications as targets for new anticancer drugs. (Review)
S. Schäfer, M. Jung; Arch. Pharm. Chem. Life Sci. 338 (2005), 347-357.

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Histone deacetylase inhibitors

Amide Analogues of Trichostatin A as Inhibitors of Histone Deacetylase and Inducers of Terminal Cell Differentiation.
M. Jung G. Brosch, D. Kölle, H. Scherf, C. Gerhäuser, P. Loidl; J. Med. Chem. 42 (1999), 4669-4679.

Induction of human gamma globin gene expression by histone deacetylase inhibitors.
H. Cao, G. Stamatoyannopoulos, M. Jung; Blood 103 (2004), 701-709.

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Histone deacetylase substrates and assays

A Non-Isotopic Assay for Histone Deacetylase Activity.
K. Hoffmann, G. Brosch, P. Loidl, M. Jung; Nucleic Acids Res. 27 (1999), 2057-2058.

A homogeneous non-isotopic histone deacetylase activity assay.
B. Heltweg, M. Jung; J. Biomol. Screen. 8 (2003), 89-95.

Subtype selective substrates for histone deacetylases.
B. Heltweg, F. Dequiedt, B. L. Marshall, C. Brauch, M. Yoshida, N. Nishino, E. Verdin, M. Jung;
J. Med. Chem. 47 (2004), 5235-5243.

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Sirtuin inhibitors

SIRT1 regulates HIV transcription via Tat deacetylation.
S. Pagans, A. Pedal, B. J. North, K. Kaehlcke, B. L. Marshall, A. Dorr, C. Hetzer-Egger, P. Henklein, R. Frye, M. W. McBurney, H. Hruby, M. Jung, E. Verdin, M. Ott; PLoS Biology 3 (2005), e41.

Adenosine mimics as inhibitors of NAD+-dependent histone deacetylases - from kinase to sirtuin inhibitors.
J. Trapp, A. Jochum, R. Meier, L. Saunders, B. Marshall, E. Verdin, P. Goekjian, C. Kunick, W. Sippl, M. Jung;
J. Med. Chem. 49 (2006), 7307-7316.

Structure activity studies on suramin analogues as inhibitors of NAD+-dependent histone deacetylases (sirtuins).
J. Trapp, R. Meier, D. Hongwiset, M. U. Kassack,W. Sippl, M. Jung; ChemMedChem. 2 (2007), 1419-1431.

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HAT inhibitors

Characterization of novel inhibitors of histone acetyltransferases.
E. Eliseeva, V. Valkov, M. Jung, M. Jung; Mol. Cancer Ther. 6 (2007), 2391-2398.

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Histon methyltransferase inhibitors

Target-based approach to inhibitors of histone arginine methyltransferases.
A. Spannhoff, R. Heinke, I. Bauer, P. Trojer, E. Metzger, R. Gust, R. Schüle, G. Brosch, W. Sippl, M. Jung, ;
J. Med. Chem. 50 (2007), 2319-2325.

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