Cell Chemical Biology p. 1490 - 11,1500 (2017)
Update date:2022-08-18
Topics:
Lamberto, Ilaria
Liu, Xiaoxi
Seo, Hyuk-Soo
Schauer, Nathan J.
Iacob, Roxana E.
Hu, Wanyi
Das, Deepika
Mikhailova, Tatiana
Weisberg, Ellen L.
Engen, John R.
Anderson, Kenneth C.
Chauhan, Dharminder
Dhe-Paganon, Sirano
Buhrlage, Sara J.
Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5–10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies. Due to a lack of high-resolution DUB?small-molecule ligand complex structures, no structure-guided optimization efforts have been reported for a mammalian DUB. Here, we report a small-molecule?ubiquitin-specific protease (USP) family DUB co-structure and rapid design of potent and selective inhibitors of USP7 guided by the structure. Interestingly, the compounds are non-covalent active-site inhibitors. Lamberto et al. report the structure-guided development of inhibitors of the deubiquitinating enzyme (DUB) USP7. The studies provide optimized and well-characterized probes for studying USP7 in normal and disease biology and, furthermore, lend validation to the notion that potent and selective active-site inhibitors of DUBs can be achieved.
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