Developing Spindlin1 small-molecule inhibitors by using protein microarrays.
Nat Chem Biol
; 13(7): 750-756, 2017 Jul.
Article
em En
| MEDLINE
| ID: mdl-28504676
ABSTRACT
The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. The small-molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains and, with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs, we screened a protein-domain microarray of human methyllysine effector molecules to rapidly detect compounds with new binding profiles with either increased or decreased specificity. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor-domain-containing protein Spindlin1 (SPIN1). Structural studies facilitated the rational synthesis of SPIN1 inhibitors with increased selectivity (EML631-633), which engage SPIN1 in cells, block its ability to 'read' H3K4me3 marks and inhibit its transcriptional-coactivator activity. Protein microarrays can thus be used as a platform to 'target-hop' and identify small molecules that bind and compete with domain-motif interactions.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Piperidinas
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Benzamidas
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Proteínas de Ciclo Celular
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Análise Serial de Proteínas
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Bibliotecas de Moléculas Pequenas
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Proteínas Associadas aos Microtúbulos
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article