Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor.
J Med Chem
; 65(4): 3173-3192, 2022 02 24.
Article
em En
| MEDLINE
| ID: mdl-35167750
ABSTRACT
Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer. While long drug-target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors have been reported. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor, RMS-07, targeting a poorly conserved cysteine in the kinase's hinge region. RMS-07 shows potent MPS1 inhibitory activity and selectivity against all protein kinases with an equivalent cysteine but also in a broader kinase panel. We demonstrate potent cellular target engagement and pronounced activity against various cancer cell lines. The covalent binding mode was validated by mass spectrometry and an X-ray crystal structure. This proof of MPS1 covalent ligandability may open new avenues for the design of MPS1-specific chemical probes or drugs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Tirosina Quinases
/
Proteínas Serina-Treonina Quinases
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Proteínas de Ciclo Celular
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Inibidores de Proteínas Quinases
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Antineoplásicos
Limite:
Animals
/
Female
/
Humans
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Male
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2022
Tipo de documento:
Article