A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader.
Cell Chem Biol
; 25(1): 88-99.e6, 2018 01 18.
Article
em En
| MEDLINE
| ID: mdl-29129717
ABSTRACT
Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. In this study, we designed a multi-kinase degrader by conjugating a highly promiscuous kinase inhibitor with a cereblon-binding ligand, and used quantitative proteomics to discover 28 kinases, including BTK, PTK2, PTK2B, FLT3, AURKA, AURKB, TEC, ULK1, ITK, and nine members of the CDK family, as degradable. This set of kinases is only a fraction of the intracellular targets bound by the degrader, demonstrating that successful degradation requires more than target engagement. The results guided us to develop selective degraders for FLT3 and BTK, with potentials to improve disease treatment. Together, this study demonstrates an efficient approach to triage a gene family of interest to identify readily degradable targets for further studies and pre-clinical developments.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteômica
/
Inibidores de Proteínas Quinases
/
Tirosina Quinase 3 Semelhante a fms
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Tirosina Quinase da Agamaglobulinemia
Limite:
Humans
Idioma:
En
Revista:
Cell Chem Biol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos