Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.
J Med Chem
; 63(2): 656-675, 2020 01 23.
Article
em En
| MEDLINE
| ID: mdl-31858797
ABSTRACT
WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Quinolonas
/
Compostos Bicíclicos Heterocíclicos com Pontes
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Peptídeos e Proteínas de Sinalização Intracelular
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Repetições WD40
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article