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Day 2 Oral Communications I

Chair: Prof. Andrew Marston, University of Geneva
 

Lectures and Oral Communications in Red are from members of our Consortium.

 

Discovery and development of kinase inhibitors
Prof. Dr. Conrad Kunick, University of Braunschweig, Germany
 

Protein Kinase Inhibitors: New Drugs for the Human Parasite Leishmania
Prof. Charles Jaffe, The Hebrew University of Jerusalem, Israel
 

Protein Kinase C epsilon
Prof. Johann Hofmann, Innsbruck Medical University, Austria
 

Strategies for the discovery of new plant-derived kinase inhibitors
Prof. Andrew Marston, University of Geneva, Switzerland
 

Novel kinase inhibitors for the survival IGF1R/PKB pathway
Prof. Alexander Levitzki, The Hebrew University of Jerusalem, Israel

Certain privileged structures are frequently found as basic pharmacophores in ATP competitive kinase inhibitors, e.g. indolinones, purines, maleimides, and quinazolines. These classic generic templates occupy an area within the ATP binding cleft where they are hold in position by hydrogen bonds to amino acids from the hinge region. In the paullone family of kinase inhibitors the mentioned elements are replaced by a 1-benzazepin-2(1H)-one partial structure. With a view to investigate the suitability of this element as general adenino mimetic pharmacophore, a library of compounds focused on the said heterocyclic scaffold was tested on an array of cancer-related human kinases. The results yielded several new kinase inhibitory chemical entities. However, it was concluded that not in all of these inhibitors the 1-benzazepin-2(1H)-one actually serves as the adenine mimicking motif.
 

Protein Kinase Inhibitors: New Drugs for the Human Parasite Leishmania
Prof. Charles Jaffe, The Hebrew University of Jerusalem, Israel

Orly Shimony1, Paul Pechan2, Mireck Strnad3 & Charles L Jaffe1 –
1 Department of Parasitology, Hebrew University-Hadassah Medical School, Jerusalem, Israel;
2 C3Bio, Munich, Germany;
3 Laboratory of Growth Regulators, Palacky University and Institute of Experimental Botany ASCR,
Olomouc, Czech Republic
 

Over 21 species of Leishmania cause morbidity and mortality in humans. Existing drugs are toxic, and the emerging resistance emphasizes the need for new therapeutic agents. Compounds that inhibit protein kinases were screened for activity against Leishmania using a rapid fluorescent viability assay with Alamar Blue.

Initially, 30 compounds were tested at 50 mM on promastigotes (extracellular) and amastigotes (intracellular) of L. donovani and L. tropica. Differences in activity on both stages and species were observed, and only one compound inhibited growth, >80%, of all stages and species. After analysis additional analogs were selected. All 119 compounds were screened on L. donovani amastigotes at 30 mM. Six compounds inhibited growth ≥80%. Based on structure-function analysis an additional 15 compounds were synthesized and tested. Inhibition ≥80% by 15 and three of the new compounds at 30 and 15 mM, respectively, was observed. Synthesis and testing of new more effective analogs is in progress.

 

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Protein Kinase C epsilon
Prof. Johann Hofmann, Innsbruck Medical University, Austria

Johann Hofmann, Dorota Garczarczyk, Florian Rechfeld & Georg Hechenberger
Biocenter, Division of Medical Biochemistry, Innsbruck Medical University, Innsbruck, Austria

Protein kinase C (PKC) comprises a phospholipid-dependent serine/threonine kinase family of 10 related isozymes. Their precise function is not known at present. PKC epsilon has been reported to be involved in malignant transformation, protection from ischemic insult, cardiac hypertrophy, macrophage activation, nociceptor function and alcohol consumption. Major targets of PKC epsilon seem to be the Raf1- Elk1-pathway and nucleophosmin (involved in centrosome duplication and malignant transformation). Following activation, PKC epsilon is transported from the cytosol and the Golgi to the plasma membrane by RACK2 (receptor of activated C kinase). Tetracycline-induced overexpression of constitutively active PKC epsilon in HeLa cells led to overexpression of one, and to down-modulation of approximately 30 sequences. The upregulated full-length sequence is a peptidyl-prolyl cis–trans isomerase (involved in protein folding), the two down-modulated sequences are C6orf69 and RHOBTB3. Both contain BTB/POZ domains, involved in protein–protein interactions or transcriptional regulation.

 

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Strategies for the discovery of new plant-derived kinase inhibitors
Prof. Andrew Marston, University of Geneva, Switzerland

Kurt Hostettmann & Andrew Marston
Laboratory of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences,
University of Geneva, University of Lausanne, Geneva, Switzerland
 

About 35% of prescribed medicines in industrialized countries are of natural origin. New drugs have been recently introduced which are based on chemically defined plant constituents and include the anticancer agents paclitaxel from the Pacific yew Taxus brevifolia (Taxaceae). Artemisinin, a sesquiterpene lactone from the Chinese plant Artemisia annua (Asteraceae), is now being successfully used for the treatment of malaria and galanthamine, an alkaloid from the snowdrop (Galanthus nivalis, Amaryllidaceae), has just been released for the management of Alzheimer’s disease. As far as biochemical tools from nature are concerned, the alkaloid staurosporine isolated from microbial sources is a strong, non-selective inhibitor of protein kinase C and also inhibits other protein kinases.

Since more than 350,000 species of higher plants have been identified and only 10% have been investigated from both a phytochemical and pharmacological point of view, a vast potential exists for the discovery of new compounds. These can be targeted by biological and chemical screening of extracts. The chemical screening employs an array of hyphenated HPLC techniques (LC/UV, LC/MS, LC/NMR) (Hostettmann et al., 2003) for the rapid identification of constituents in crude plant extracts.

This approach will be discussed and illustrated with reference to the search for new kinase inhibitors.

 

Novel kinase inhibitors for the survival IGF1R/PKB pathway
Prof. Alexander Levitzki, Unit of Cellular Signaling,
Department of Biological Chemistry,
The Alexander Silberman Institute of Life Sciences,

During the past 2 years we have developed a series of novel inhibitors against IGF1R, PKB/Akt and Jak-2. Most of the progress has been made in the development of the IGF1R and PKB/Akt. Although very different chemically, the common denominator of the two classes of inhibitors is that they are substrate competitive and highly non-toxic. In the presentation (I will elaborate on the chemistry and properties of these inhibitors. The type of cell-free assay, utilized for the screening for Jak-2 inhibitors will also be described.

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