Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead.
Cell Chem Biol
; 25(1): 78-87.e5, 2018 01 18.
Article
em En
| MEDLINE
| ID: mdl-29129718
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 PROTACtarget protein affinity can be stabilized by high-affinity targetPROTACligase 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
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Ubiquitina-Proteína Ligases
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Complexo de Endopeptidases do Proteassoma
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Inibidores de Proteínas Quinases
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Bibliotecas de Moléculas Pequenas
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article