Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders.
J Med Chem
; 64(15): 10682-10710, 2021 08 12.
Article
en En
| MEDLINE
| ID: mdl-33980013
ABSTRACT
Histone H3K4 methylation serves as a post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferase (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat-containing protein 5 (WDR5) that has also been associated with controlling long noncoding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMT complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic functions. This study presents the design, synthesis, and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Compuestos de Bifenilo
/
Dihidropiridinas
/
Diseño de Fármacos
/
Péptidos y Proteínas de Señalización Intracelular
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Alemania