Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with Strong In Vivo Antitumor Activity.
J Med Chem
; 63(9): 4997-5010, 2020 05 14.
Article
em En
| MEDLINE
| ID: mdl-32338903
ABSTRACT
Targeting the menin-MLL protein-protein interaction is a new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein the structure-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 (16) as a highly potent and efficacious covalent menin inhibitor. M-808 effectively inhibits leukemia cell growth at low nanomolar concentrations and is capable of achieving partial tumor regression in an MV4;11 xenograft tumor model in mice at a well-tolerated dose schedule. Determination of the co-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinity, covalent interactions. M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation toward developing a new therapy for the treatment of MLL leukemia.
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Base de dados:
MEDLINE
Assunto principal:
Ligação Proteica
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Azetidinas
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Leucemia Mieloide Aguda
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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
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article