Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction.
Angew Chem Int Ed Engl
; 57(6): 1601-1605, 2018 02 05.
Article
em En
| MEDLINE
| ID: mdl-29284071
ABSTRACT
The structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction is presented. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co-crystal structure of M-525 in complex with menin firmly establish its mode of action. A single administration of M-525 effectively suppresses MLL-regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M-525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Histona-Lisina N-Metiltransferase
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Proteínas Proto-Oncogênicas
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Proteína de Leucina Linfoide-Mieloide
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos