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Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead.
- Source :
-
Cell Chemical Biology . Jan2018, Vol. 25 Issue 1, p78-87.e5. 1p. - Publication Year :
- 2018
-
Abstract
- Summary Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases. In contrast, weak PROTAC:target protein affinity can be stabilized by high-affinity target:PROTAC:ligase trimer interactions, leading to efficient degradation. This study highlights design guidelines for generating potent PROTACs as well as possibilities for degrading undruggable proteins immune to traditional small-molecule inhibitors. [ABSTRACT FROM AUTHOR]
- Subjects :
- *DRUG development
*PROTEINS
*PROTEOLYSIS
*CHIMERISM
*UBIQUITINATION
Subjects
Details
- Language :
- English
- ISSN :
- 24519456
- Volume :
- 25
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Cell Chemical Biology
- Publication Type :
- Academic Journal
- Accession number :
- 127286777
- Full Text :
- https://doi.org/10.1016/j.chembiol.2017.09.010