High-affinity small-molecule inhibitors of the menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein interaction.
J Med Chem
; 57(4): 1543-56, 2014 Feb 27.
Article
em En
| MEDLINE
| ID: mdl-24472025
ABSTRACT
The protein-protein interaction (PPI) between menin and mixed lineage leukemia (MLL) plays a critical role in acute leukemias, and inhibition of this interaction represents a new potential therapeutic strategy for MLL leukemias. We report development of a novel class of small-molecule inhibitors of the menin-MLL interaction, the hydroxy- and aminomethylpiperidine compounds, which originated from HTS of â¼288000 small molecules. We determined menin-inhibitor co-crystal structures and found that these compounds closely mimic all key interactions of MLL with menin. Extensive crystallography studies combined with structure-based design were applied for optimization of these compounds, resulting in MIV-6R, which inhibits the menin-MLL interaction with IC50 = 56 nM. Treatment with MIV-6 demonstrated strong and selective effects in MLL leukemia cells, validating specific mechanism of action. Our studies provide novel and attractive scaffold as a new potential therapeutic approach for MLL leukemias and demonstrate an example of PPI amenable to inhibition by small molecules.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteína de Leucina Linfoide-Mieloide
/
Bibliotecas de Moléculas Pequenas
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article