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Cell Chem Biol. 2018 Jan 18;25(1):78-87.e5. doi: 10.1016/j.chembiol.2017.09.010. Epub 2017 Nov 9.

Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead.

Author information

1
Department of Molecular, Cellular, and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT 06511, USA.
2
Arvinas, LLC, 5 Science Park, New Haven, CT 06511, USA.
3
Department of Molecular, Cellular, and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT 06511, USA; Departments of Chemistry and Pharmacology, Yale University, New Haven, CT, USA. Electronic address: craig.crews@yale.edu.

Abstract

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.

KEYWORDS:

CRBN; MAPK/p38; PROTACs; VHL; chemical biology; protein degradation; protein-protein interactions; proteomics; selective degradation; ternary complex

PMID:
29129718
PMCID:
PMC5777153
[Available on 2019-01-18]
DOI:
10.1016/j.chembiol.2017.09.010

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