Discovery of an MLLT1/3 YEATS Domain Chemical Probe.
Angew Chem Int Ed Engl
; 57(50): 16302-16307, 2018 12 10.
Article
em En
| MEDLINE
| ID: mdl-30288907
ABSTRACT
YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3-histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Proteínas Nucleares
/
Bibliotecas de Moléculas Pequenas
/
Proteínas de Neoplasias
Limite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Reino Unido