A benzoxazole compound as a novel MEK inhibitor for the treatment of RAS/RAF mutant cancer.
Int J Cancer
; 145(2): 586-596, 2019 07 15.
Article
em En
| MEDLINE
| ID: mdl-30628057
ABSTRACT
Mutations in RAS/RAF occur in large portion of malignancies and are associated with aggressive clinical behaviors and poor prognosis. Therefore, we developed a novel benzoxazole compound (KZ-001) as a highly potent and selective MEK 1/2 inhibitor. Our efforts were focused on enhancing the activity of the known MEK inhibitor AZD6244 and overcoming the shortcomings existing in current MEK inhibitors. Here we show that compound KZ-001 exhibits approximately 30-fold greater inhibition against BRAF- and KRAS-mutant tumor cells than that of AZD6244. These results were also demonstrated using in vivo xenograft models. Furthermore, pharmacokinetics (PK) analysis was performed for KZ-001, and this compound showed good orally bioavailability (28%) and exposure (AUC0-∞ = 337 ± 169 ng h/mL). To determine its potential clinical application, the synergistic effect of KZ-001 with other agents was investigated both in vitro and in vivo (xenograft models). KZ-001 exhibited synergistic anti-cancer effect in combination with BRAF inhibitor vemurafenib and a microtubule-stabilizing chemotherapeutic agent docetaxel. In addition, KZ-001 inhibited the MAPK pathway like known MEK inhibitors. In summary, KZ-001, a structurally novel benzoxazole compound, was developed as a MEK inhibitor that has potential for cancer treatment.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Benzoxazóis
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Proteínas Proto-Oncogênicas p21(ras)
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Quinases de Proteína Quinase Ativadas por Mitógeno
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Proteínas Proto-Oncogênicas B-raf
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Neoplasias
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article