RESUMEN
A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD). SCD is recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes did not activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.
Asunto(s)
Antineoplásicos/farmacología , Benzotiazoles/farmacología , Descubrimiento de Drogas/métodos , Neoplasias Pulmonares/enzimología , Ácido Oxámico/análogos & derivados , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Benzotiazoles/farmacocinética , Benzotiazoles/uso terapéutico , Benzotiazoles/toxicidad , Línea Celular Tumoral , Sistema Enzimático del Citocromo P-450/metabolismo , Familia 4 del Citocromo P450 , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones SCID , Estructura Molecular , Terapia Molecular Dirigida , Ácido Oxámico/farmacocinética , Ácido Oxámico/farmacología , Ácido Oxámico/uso terapéutico , Ácido Oxámico/toxicidad , Unión Proteica , Glándulas Sebáceas/efectos de los fármacos , Glándulas Sebáceas/enzimología , Glándulas Sebáceas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Porcupine is a member of the membrane-bound O-acyltransferase family of proteins. It catalyzes the palmitoylation of Wnt proteins, a process required for their secretion and activity. We recently disclosed a class of small molecules (IWPs) as the first reported Porcn inhibitors. We now describe the structure-activity relationship studies and the identification of subnanomolar inhibitors. We also report herein the effects of IWPs on Wnt-dependent developmental processes, including zebrafish posterior axis formation and kidney tubule formation.