Rational modification, synthesis and biological evaluation of 3,4-dihydroquinoxalin-2(1H)-one derivatives as potent and selective c-Jun N-terminal kinase 3 (JNK3) inhibitors.
Eur J Med Chem
; 201: 112445, 2020 Sep 01.
Article
en En
| MEDLINE
| ID: mdl-32603981
ABSTRACT
The c-Jun N-terminal kinase 3 (JNK3) plays key roles in a wide range of diseases, including neurodegeneration diseases, inflammation diseases, cancers, cardiovascular diseases, and metabolic disorders. Previously, we have identified a lead compound, (Z)-3-(2-(naphthalen-1-yl)-2-oxoethylidene)-3,4-dihydroquinoxalin-2(1H)-one (J46), which contains a 3,4-dihydroquinoxalin-2(1H)-one core structure as a key fragment to inhibit JNK3. However, compound J46 displayed high DDR1 and EGFR (T790M, L858R) inhibition and poor physicochemical properties, especially clogD and water-solubility, in its biological studies. Herein, we optimized compound J46 by structure-based drug design and exploiting the selectivity and physicochemical properties of various warhead groups to obtain compound J46-37, which not only exhibited a potent inhibition against JNK3 but also showed more than 50-fold potency better than DDR1 and EGFR (T790M, L858R). Furthermore, the selectivity and structure-activity relationship of novel synthesized 3,4-dihydroquinoxalin-2(1H)-one derivatives were analyzed by molecular docking and molecular dynamics simulation. Overall, compound J46-37, as a highly selective inhibitor of JNK3 with well physicochemical properties, is worth developing as therapies for the treatment of diseases related to JNK3.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Quinoxalinas
/
Proteína Quinasa 10 Activada por Mitógenos
/
Inhibidores de Proteínas Quinasas
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2020
Tipo del documento:
Article
País de afiliación:
China