Identification of non-ATP-competitive α-carboline inhibitors of the anaplastic lymphoma kinase.
Eur J Med Chem
; 238: 114488, 2022 Aug 05.
Article
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| MEDLINE
| ID: mdl-35665691
ABSTRACT
The Anaplastic Lymphoma Kinase (ALK) is a therapeutic target for personalized medicine in selected cancers. Despite excellent clinical responses to ALK inhibitors, most patients develop drug resistance and relapse. New compounds with alternative binding modes are needed to overcome resistant mutants. Here we describe a medicinal chemistry effort to the design and development of novel ALK inhibitors based on a 4,6-substituted α-carboline scaffold. Active compounds were able to inhibit the gatekeeper L1196M mutant, in several cases better than the wild-type enzyme. Compound 43 showed potent non-ATP-competitive inhibition of wild-type and mutant ALK, including G1202R, in biochemical and cellular assays, as well as in xenograft mouse models.
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Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Carbolinas
/
Proteínas Tirosina Quinasas Receptoras
Tipo de estudio:
Diagnostic_studies
Idioma:
En
Revista:
Eur J Med Chem
Año:
2022
Tipo del documento:
Article