Identification of 2,6-Disubstituted 3H-Imidazo[4,5-b]pyridines as Therapeutic Agents for Dysferlinopathies through Phenotypic Screening on Patient-Derived Induced Pluripotent Stem Cells.
J Med Chem
; 62(20): 9175-9187, 2019 10 24.
Article
en En
| MEDLINE
| ID: mdl-31550153
ABSTRACT
Dysferlinopathies, which are muscular diseases caused by mutations in the dysferlin gene, remain serious medical problems due to the lack of therapeutic agents. Herein, we report the design, synthesis, and structure-activity relationships of a 2,6-disubstituted 3H-imidazo[4,5-b]pyridine series, which was identified from the phenotypic screening of chemicals that increase the level of dysferlin in myocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs). Optimization studies with cell-based phenotypic assay led to the identification of a highly potent compound, 19, with dysferlin elevation effects at double-digit nanomolar concentrations. In addition, the molecular target of our chemical series was identified as tubulin, through a tubulin polymerization assay and a competitive binding assay using a photoaffinity labeling probe.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Piridinas
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Distrofia Muscular de Cinturas
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Moduladores de Tubulina
/
Imidazoles
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
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Screening_studies
Límite:
Humans
Idioma:
En
Año:
2019
Tipo del documento:
Article