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Medicinal Chemistry

AG Sippl December 2015

AG Sippl December 2015

AG Sippl December 2015

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Histone acetyltransferase inhibitors block neuroblastoma cell growth in vivo

We have previously described novel histone acetyltransferase (HAT) inhibitors that block neuroblastoma cell growth in vitro. Herewe show that two selected pyridoisothiazolone HAT inhibitors, PU139 and PU141, induce cellular histone hypoacetylation andinhibit growth of several neoplastic cell lines originating from different tissues. Broader in vitro selectivity profiling shows thatPU139 blocks the HATs Gcn5, p300/CBP-associated factor (PCAF), CREB (cAMP response element-binding) protein (CBP) and p300,whereas PU141 is selective toward CBP and p300. The pan-inhibitor PU139 triggers caspase-independent cell death in cell culture.Both inhibitors block growth of SK-N-SH neuroblastoma xenografts in mice and the PU139 was shown to synergize withdoxorubicin in vivo. The latter also reduces histone lysine acetylation in vivo at concentrations that block neoplastic xenograftgrowth. This is one of the very few reports on hypoacetylating agents with in vivo anticancer activity.

Full text - Open access:

Oncogenesis (2015) 4, e137; doi:10.1038/oncsis.2014.51   


New DFG-funded project "Structure based development and biological characterization of selective inhibitors of histone deacetylases (HDACs) 8 and 10"

The Deutsche Forschungsgemeinschaft (DFG) is funding a new joint project of the Sippl group together with M. Jung (University of Freiburg), I. Oehme and O. Witt (DKFZ Heidelberg) on the optimization of inhibitors of the histone deacetylase (HDAC) subtypes 8 and 10. Histone deacetylases are important modulators of epigenetic gene regulation and 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. In previous work,  HDACs 8 and 10 were identified as promising anticancer targets and respective inhibitors as candidates for further optimization. Crystal structures of HDAC8 and homologues in complex with inhibitors as well as homology models of HDAC10 will be used for structure- and computer-based optimization of the lead structures. Within this project we will further investigate the role of HDAC8 and 10 in the proliferation of cancer cells and optimize available lead structures in a bioguided fashion for potency and selectivity, both in-vitro and in cell culture. Selected improved inhibitors will be subjected to animal studies to clarify the potential of HDAC8 and 10 for future drug development.


Meeting Strasbourg

Meeting Strasbourg

Meeting Strasbourg

A-ParaDDisE project
Kick-Off meeting, Strasbourg, March 17-18, 2014

The kick-off meeting for the A-ParaDDisE project (EC, FP7-Health) took place in the auditorium of the IGBMC in Illkirch, near Strasbourg on March 17-18. It was hosted by the GIE-CERBM and Dr. Christophe Romier, and the participants were warmly welcomed by the director of the IGBMC (Bertrand Séraphin) and the head of the Structural and Integrative Biology group (Patrick Schultz). Chris Romier gave an introductory presentation of the IGBMC, its history, departments and infrastructures and officially inaugurated the meeting. All participants were unanimous in their praise for the efficient organization of the meeting by the host, which ensured that extremely open and informative discussions could take place. The programme allowed for the presentation of an overview of the project by the coordinator, followed by individual presentations by the project participants and detailed discussions of each Work Package in order to set out strategies for collaborations and material transfers between the teams involved.


Logo EU-Projekt A-PARADDISE

Logo EU-Projekt A-PARADDISE

02/2014 - New EU consortium on Epigenetic anti-parasite drugs

Within the framework of FP-7, the consortium A-PARADDISE (Anti-parasitic drug discovery in epigenetics) will unite 16 groups from seven countries (Australia, Brazil, France, Germany, Italy, Sweden, UK) to discover new drugs against the major parasites Schistosoma, Plasmodium, Leishmania and Trypanosma using the epigenetic machinery of these pathogens. A-PARADDISE website (http://a-paraddise.cebio.org/   ). German press release. http://pressemitteilungen
hallelife.de

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Preis für Claudia Henze

Auszeichnung für Diplom-Pharmazeutin Claudia Henze

Preis für die beste Diplomarbeit der Serumwerk Bernburg AG geht an  Diplom-Pharmazeutin Claudia Henze aus der Abteilung Medizinische Chemie.

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Auszeichnung für Alexander Rohe

Auszeichnung für Apotheker Alexander Rohe

Martin-Luckner Preis und  Preis für die beste Diplomarbeit der Serumwerk Bernburg AG 2010/11 geht  an Apotheker Alexander Rohe aus der Abteilung Medizinische Chemie.

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New Themed Issue "Epigenetics" in MedChemComm

MedChemComm is delighted to publish this collection of articles in the emerging field of epigenetics research, guest edited by Dr Mark Bunnage (Pfizer) and Professor Rasmus Prætorius Clausen (University of Copenhagen).

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Since October 1st 2011 Prof. Wolfgang Sippl is visiting professor at the FRIAS (Freiburg Institute for Advanced Studies) of the Freiburg University.

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Funding of a new interdisciplinary research cluster "Structure-based epigenetic drug discovery"

The FRIAS at the University of Freiburg is funding a new  interdisciplinary research cluster focussing on “Structure-based Epigenetic Drug Discovery”.

The applicants will  establish the foundation for structure-based epigenetic drug  discovery in Freiburg based upon their expertises in structural  biochemistry (Prof. Oliver Einsle; Univ. Freiburg), medicinal chemistry (Prof. Manfred  Jung, Univ. Freiburg) and cheminformatics (Prof. Wolfgang Sippl, MLU Halle-Wittenberg). Based on the close  interaction of the individual research areas a number of lead structures  for epigenetic targets will be developed and made available for further  biological characterization.

The Freiburg Institute for  Advanced Studies (FRIAS) is the University of  Freiburg’s international  research college. It was established after  Freiburg’s success in the  Federal Excellence Initiative in October 2007.

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Wettlauf gegen die Resistenz

Campus News in der Mitteldeutschen Zeitung

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Developmemt of an open-source protein-ligand docking platform



The software ParaDockS is a framework for molecular docking.

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Contact

Institut für Pharmazie
Institutsbereich Pharmazeutische Chemie und Klinische Pharmazie
Abteilung Medizinische Chemie
Leiter: Prof. Dr. Wolfgang Sippl

Wolfgang-Langenbeck-Str. 4
06120 Halle (Saale)

phone: +49-345-55-25040
fax: +49-345-55-27355

postal address:
Institut für Pharmazie
Institutsbereich Pharmazeutische Chemie und Klinische Pharmazie
Abteilung Medizinische Chemie
06120 Halle (Saale)

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