RESUMEN
The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.
Asunto(s)
Benzamidas/farmacología , Ciclo Celular/efectos de los fármacos , Neoplasias del Colon/patología , Neoplasias del Colon/fisiopatología , Inhibidores Enzimáticos/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Benzamidas/uso terapéutico , Cadherinas/análisis , Proteínas Quinasas Dependientes de Calcio-Calmodulina/antagonistas & inhibidores , División Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/enzimología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Femenino , Factor de Crecimiento de Hepatocito/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos , Ratones Desnudos , Invasividad Neoplásica/prevención & control , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
Mutational activation of ras has been found in many types of human cancers, including a greater than 50% incidence in colon and about 90% in pancreatic carcinomas. The activity of both native and oncogenic ras proteins requires a series of post-translational processing steps. The first event in this process is the farnesylation of a cysteine residue located in the fourth position from the carboxyl terminus of the ras protein, catalyzed by the enzyme farnesyltransferase (FTase). Inhibitors of FTase are potential candidates for development as antitumor agents. Through a high-volume screening program, the pentapeptide derivative PD083176 (1), Cbz-His-Tyr(OBn)-Ser(OBn)-Trp-DAla-NH2, was identified as an inhibitor of rat brain FTase, with an IC50 of 20 nM. Structure-activity relationships were carried out to determine the importance of the side chain and chirality of each residue. This investigation led to a series of potent FTase inhibitors which lack a cysteine residue as found in the ras peptide substrate. The parent compound (1) inhibited the insulin-induced maturation of Xenopus oocytes (concentration: 5 pmol/oocyte), a process which is dependent on the activation of the ras pathway.