Discovery of Ureido-Substituted 4-Phenylthiazole Derivatives as IGF1R Inhibitors with Potent Antiproliferative Properties.
Molecules
; 29(11)2024 Jun 04.
Article
en En
| MEDLINE
| ID: mdl-38893528
ABSTRACT
The existing kinase inhibitors for hepatocellular carcinoma (HCC) have conferred survival benefits but are hampered by adverse effects and drug resistance, necessitating the development of novel agents targeting distinct pathways. To discover potent new anti-HCC compounds, we leveraged scaffold hopping from Sorafenib and introduced morpholine/piperidine moieties to develop ureido-substituted 4-phenylthiazole analogs with optimized physicochemical properties and binding interactions. Notably, compound 27 exhibited potent cytotoxicity against HepG2 cells (IC50 = 0.62 ± 0.34 µM), significantly exceeding Sorafenib (IC50 = 1.62 ± 0.27 µM). Mechanistic investigations revealed that compound 27 potently inhibited HCC cell migration and colony formation, and it induced G2/M arrest and early-stage apoptosis. Kinase profiling revealed IGF1R as a key target, which compound 27 potently inhibited (76.84% at 10 µM). Molecular modeling substantiated compound 27's strong binding to IGF1R via multiple hydrogen bonds. Computational predictions indicate favorable drug-like properties for compound 27. These findings provide a promising drug candidate for the treatment of HCC patients.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tiazoles
/
Receptor IGF Tipo 1
/
Apoptosis
/
Inhibidores de Proteínas Quinasas
/
Proliferación Celular
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Molecules
Asunto de la revista:
BIOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Suiza