Key words
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Cheminformatics; drug design; kinase inhibitors; anticancer agents; virtual screening; angiogenesis
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Research programs
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COST-Action CM0602 - Inhibitors of angiogenesis: design, synthesis and biological exploitation
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Short description
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This project is part of the COST Action CM0602 'Angiokem' aimed at coordinating research on the development of anti-angiogenic compounds, in particular inhibitors of receptor tyrosine kinases, for treating cancer. Although several such inhibitors are already in the clinic, it is still necessary to search for new inhibitor types due to the frequent occurrence of drug resistance. The COST 'Angiokem' network combines competences in cheminformatics, drug design, organic synthesis, cancer biology, ioassay and clinical development of drugs. The present research proposal aims to discover new small molecule inhibitors of tyrosine kinases by combining cheminformatics methods developed by REYMOND, University of Berne, Switzerland, and GOLDBLUM, Hebrew University of Jerusalem, Israel. These methods will be used to identify promising compounds in silico, which will then be synthesized in the laboratory of BOSCH and AMAT in Barcelona, Spain, and tested for kinase inhibition by the group of DONO and MAINA in Marseilles, France. These groups are participating in the COST action Angiokem'. We will use cheminformatics tool developed in the REYMOND group to generate large databases of analogs of known tyrosine kinase inhibitors and use virtual screening to identify promising new ligands for synthesis and testing. One projects aims at two known inhibitors of the receptor tyrosine kinases VEGFR-2 and Tie-2, using systematic substructure replacement to find optimal analogs of the compounds. The second project will explore the chemical space of general kinase inhibitors by systematic generation of heterocyclic analogs of adenine. The third project focuses on inhibitors of c- MET, a tyrosine kinaes implicated in resistance to VEGFR2 inhibitor resistance. In all three project the workflow comprises virtual database generation, scoring of the compounds using docking and other scoring functions, and selection of synthetic targets.
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Further information
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Full name of research-institution/enterprise: Universität Bern Departement für Chemie und Biochemie
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Partners and International Organizations
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BE, CH, CY, CZ, DE, DK, ES, FR, GR, HR, IE, IL, IT, NO, PL, RS, SE, SI, SK, TR, UK
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Abstract
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This project was part of the COST Action CM0602 'Angiokem' aimed at coordinating research on the development of anti-angiogenic compounds, in particular inhibitors of receptor tyrosine kinases, for treating cancer. Our group participated in the action within the working group 4 on “Advanced drug design approaches (in silico methodologies, modern medicinal chemistry methods, activity bioassays)” by its expertise in the area of virtual library generation and screening. We were involved in a project focusing on identifying anti-angiogenic kinase inhibitors. We used virtual screening to identify promising ligands for synthesis and testing. Several active molecules were identified through collaborations with biologists within Angiokem. Two students were directly supported by the project, namely Ruud van Deursen, who finished his Ph.D. thesis in spring 2010, and from Mai 2010 Lars Ruddigkeit, then a beginning graduate student. An additional screening campaign was conducted by Stefanie Buschor, a MS student in our laboratory, who was awarded an STSM in the laboratory of Prof. Breandan Kennedy in Dublin, which has led to identification of two new series of antiangiogenic compounds which will be the object of further studies.
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References in databases
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Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. +41 31 322 74 82 Swiss Project-Number: C08.0024
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