FOR 1406:  Exploiting the Potential of Natural Compounds: Myxobacteria as Source for Leads, Tools and Therapeutics in Cancer Research

• Subject Area: Medicine ; Chemistry
• Term: from 2010 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 159663715

Natural products play an important role in drug discovery and biomedical research for two major reasons: Firstly, they possess an enormous structural diversity serving as privileged scaffolds in drug discovery (leads) and, secondly, they have proven to be valuable tools for examining cellular processes and identifying targets in signal transduction pathways.
However, besides this enormous potential of natural products, obstacles exist. These are mainly due to difficulties in isolation and/or synthesis in sufficient quantities and, consequently, to a lack of thorough investigations concerning their molecular mechanisms of action and their targets. Thus, the potential of natural products in pharmaceutical sciences is not yet fully exploited.
The Research Unit will meet this challenge by exemplarily focussing on natural products from myxobacteria: (1) Novel species of myxobacteria will be identified and screened for bioactive compounds.
(2) Innovative biotechnological/(bio)synthetic approaches will be used to guarantee compound supply as well as create analogs of them.
(3) Innovative in silico approaches will help to define the mode of action of the natural compounds, and to design more potent analogs.
(4) By combining chemistry with proteomics yet unknown targets of the natural compounds shall be identified.
(5) Finally, with regard to anticancer pharmacology of the myxobacterial compounds the Research Unit aims at attractive and promising avenues: It will not only focus on tumour death inducing effects of compounds, but also examine their influence on tumour cell migration as well as on cancer immunosurveillance and their underlying signalling pathways.
Moreover, besides tumour cells, vascular cells and immune cells known to play a role in cancer survival are in the centre of interest for respective pharmacological work. To this end, complex cellular and in vivo systems as well as pharmacogenomics are employed for first line characterisation of promising compounds instead of isolated target screening as usually performed in industrial drug discovery.

• DFG Programme: Research Units
• International Connection: Switzerland

Projects

• (Bio)Syntheses of chondramides and related cyclodepsipeptides (Applicants Kazmaier, Uli ;  Müller, Rolf )
• (Bio)Synthesis of archazolids and their analogs (Applicants Trauner, Dirk ;  Wenzel, Silke Christine )
• Central Management (Applicant Vollmar, Angelika )
• Central Project for Coordination, Gender Equality and Network Funding (Applicant Vollmar, Angelika )
• Computer-assisted design and characterization of natural product mimetics (Applicant Schneider, Gisbert )
• Design and synthesis of novel archazolids: Development of simplified analogues (Applicant Menche, Dirk )
• Identification, validation and functional characterization of targets of myxobacterial compounds with potential for pharmacological cancer treatment (Applicant Sieber, Stephan A. )
• Impact of archazolid on tumor metabolism (Applicant von Schwarzenberg, Karin )
• Investigations into the influence of pretubulysin and archazolid on endothelial processes responsible for tumor cell adhesion and transmigration (Applicant Fürst, Robert )
• Mode of action and prove of efficacy of myxobacterial compounds as antimetastatic agents (Applicant Vollmar, Angelika )
• Syntheses of pretubulysin derivatives for targeted tumor therapies (Applicants Kazmaier, Uli ;  Wagner, Ernst )
• Targeting of monocytes and macrophages by myxobacterial compounds as anti-cancer strategy (Applicant Werz, Oliver )

• Spokesperson: Professorin Dr. Angelika Vollmar
• Deputy: Professor Dr. Rolf Müller