The CSN complex plays a key role in various cellular pathways: through a metalloprotease activity of its Csn5 deneddylating enzyme, it regulates the activity of Cullin-RING ligases (CRLs). Indeed, Csn5 has been found amplified in many tumors, but, due to its pleiotropic effects, it is difficult to dissect its function and the involvement in cancer progression. Moreover, while growing evidences point to the neddylation function as a good target for drug development; specific inhibitors have not yet been developed for the CSN. Here, we propose the yeast Saccharomyces cerevisiae as a model system to screen libraries of small molecules as inhibitors of cullins deneddylation, taking advantage of the unique feature of this organism to survive without a functional CSN5 gene and to accumulate a fully neddylated cullin substrate. By combining molecular modeling and simple genetic tools, we were able to identify two small molecular fragments as selective inhibitors of Csn5 deneddylation function.

Cirigliano, A., Stirpe, A., Menta, S., Mori, M., Dell’Edera, D., Pick, E., et al. (2016). Yeast as a tool to select inhibitors of the cullin deneddylating enzyme Csn5. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 31(6), 1632-1637 [10.3109/14756366.2016.1160901].

Yeast as a tool to select inhibitors of the cullin deneddylating enzyme Csn5

MORI, MATTIA;
2016

Abstract

The CSN complex plays a key role in various cellular pathways: through a metalloprotease activity of its Csn5 deneddylating enzyme, it regulates the activity of Cullin-RING ligases (CRLs). Indeed, Csn5 has been found amplified in many tumors, but, due to its pleiotropic effects, it is difficult to dissect its function and the involvement in cancer progression. Moreover, while growing evidences point to the neddylation function as a good target for drug development; specific inhibitors have not yet been developed for the CSN. Here, we propose the yeast Saccharomyces cerevisiae as a model system to screen libraries of small molecules as inhibitors of cullins deneddylation, taking advantage of the unique feature of this organism to survive without a functional CSN5 gene and to accumulate a fully neddylated cullin substrate. By combining molecular modeling and simple genetic tools, we were able to identify two small molecular fragments as selective inhibitors of Csn5 deneddylation function.
Cirigliano, A., Stirpe, A., Menta, S., Mori, M., Dell’Edera, D., Pick, E., et al. (2016). Yeast as a tool to select inhibitors of the cullin deneddylating enzyme Csn5. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 31(6), 1632-1637 [10.3109/14756366.2016.1160901].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/1120416
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