Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors.
J Am Chem Soc
; 140(42): 13542-13545, 2018 10 24.
Article
em En
| MEDLINE
| ID: mdl-30285435
ABSTRACT
Reversible glycosylation of nuclear and cytoplasmic proteins is an important regulatory mechanism across metazoans. One enzyme, O-linked N-acetylglucosamine transferase (OGT), is responsible for all nucleocytoplasmic glycosylation and there is a well-known need for potent, cell-permeable inhibitors to interrogate OGT function. Here we report the structure-based evolution of OGT inhibitors culminating in compounds with low nanomolar inhibitory potency and on-target cellular activity. In addition to disclosing useful OGT inhibitors, the structures we report provide insight into how to inhibit glycosyltransferases, a family of enzymes that has been notoriously refractory to inhibitor development.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
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N-Acetilglucosaminiltransferases
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Inibidores Enzimáticos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article