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Elucidation of the molecular basis of the inhibition of microtubule dynamics


An atomic level explanation of the molecular basis of the action of anticancer agents inhibiting microtubule functions has been a long sought and yet partially unsolved goal in cancer research. In cells tubulin exists in a state of dynamic equilibrium between a heterodimeric form and a polymeric form, generally refereed to as microtubules. The intrinsic dynamic instability of microtubules is essential for their function, particularly mitosis. Compounds altering this dynamic exchange interfere with cell proliferation and are promising candidates for cancer chemotherapy. Several classes of natural products were recently observed to induce mitotic arrest by interfering with either the disassembly or assembly of the microtubule network, ultimately leading to apoptotic cell death.

Over the past decade continuous efforts were made on the elucidation of the molecular bases of the anticancer activity of tubulin-binding ligands; however, they have not provided a coherent picture. In the proposed project information on the binding conformation of microtubule-targeted depolymerising agents will be gained by novel solution NMR spectroscopic methodologies in combination with synthetic organic, computational and microscopic techniques. The localization of the pharmacon binding pockets of tubulin as well as the relative binding orientation of the ligands in their respective pockets will be assessed by a new technique (INPHARMA) recently developed by the host department. Hence, our study will, for the first time, allow systematic mapping of the binding pockets of tubulin depolymerising agents and provide description of tubulin-ligand interactions at molecular level.

Results are expected to have an impact on the development of novel anti-cancer drugs of improved activity. In addition, the postdoctoral stay will offer the researcher opportunity to broaden his scientific expertise and receive training in complementary skills necessary to lead an independent research group.

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