期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 31, 期 6, 页码 1632-1637出版社
TAYLOR & FRANCIS LTD
DOI: 10.3109/14756366.2016.1160901
关键词
CSN5/Jab1; deneddylation; fragment-based drug design; inhibitors; yeast
资金
- Associazione Gian Franco Lupo Un sorriso alla vita'' Onlus
- Israel Ministry of Science and Technology (MOST) - Italy Ministry of Foreign Affairs (MAE) grant [3-9022]
- Ateneo [C26A14XZC8]
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.
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