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Xavier Fonrose

Identification and characterization of small molecule inhibitors of the tubulin carboxypeptidase

Published on 11 June 2008


Thesis presented June 11, 2008

Abstract:
Tubulin can be cyclically modified on its alpha-subunit by enzymatic removal of the COOH-terminal tyrosine residue by tubulin carboxypeptidase (TCP) and its readdition by tubulin tyrosine ligase (TTL). Accumulation of detyrosinated tubulin is frequent in human cancers of poor prognosis. Thus, TCP could be a target for developing novel therapeutic strategies for cancers. Inhibitors of TCP, by reversing abnormal detyrosinated tubulin accumulation in tumor cells, could impair tumor progression. TCP has never been isolated and this has hampered search of specific inhibi​tors. We develop a cell-based assay of TCP activity and its use to screen two libraries of chemical compounds for their inhibitory potency. This led to the isolation of several compounds, not structurally related. Among them, parthenolide can efficiently inhibit TCP. Parthenolide is known for its anticancer properties. Thus, TCP inhibition could be one of the underlying mechanisms of these anticancer properties.

Keywords:
Microtubule, tubulin, detyrosination–tyrosination cycle, high-throughput screening, protease, inhibitor

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