RESUMEN
Click chemistry probes have improved the study of drug interactions in live cells and relevant disease models. Proper design of the probes, including the choice of the click moiety coupled to the drug, is crucial to ensure good performance and broad application. A new trans-cyclooctene derivative, amTCO, was synthesised via a novel route using a phthalimide protecting group as a built-in photosensitiser for the cyclooctene isomerization. amTCO improved the physical chemical properties of click chemistry probes compared to standard TCO moieties. An amTCO probe targeting indoleamine 2,3-dioxygenase (IDO1) was a superior tool for visualizing IDO1 and measuring the binding affinities of small molecule inhibitors to IDO1 in cells.
Asunto(s)
Ciclooctanos/farmacología , Química Clic , Ciclooctanos/química , Sistemas de Liberación de Medicamentos , Descubrimiento de Drogas , Células HeLa , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
BACKGROUND: Hypoxia-inducible factor (HIF) is an attractive therapeutic target for renal cell carcinoma (RCC) as its high expression due to the loss of von Hippel-Lindau (VHL) promotes RCC progression. Considering this, we hypothesized that ELR510444, a novel orally available small molecule inhibitor of HIF activity, would reduce angiogenesis and possess significant activity in RCC. The mechanism of action and therapeutic efficacy of ELR510444 were investigated in in vitro and in vivo models of RCC. PRINCIPAL FINDINGS: ELR510444 decreased HIF-1α and HIF-2α levels, reduced RCC cell viability and clonogenic survival, and induced apoptosis. VHL-deficient RCC cells were more sensitive to ELR510444-mediated apoptosis and restoration of VHL promoted drug resistance. Higher concentrations of ELR51044 promoted apoptosis independently of VHL status, possibly due to the microtubule destabilizing properties of this agent. ELR510444 significantly reduced tumor burden in the 786-O and A498 RCC xenograft models. These effects were associated with increased necrosis and apoptosis and inhibition of angiogenesis. CONCLUSIONS: ELR510444 is a promising new HIF inhibitor that reduced RCC cell viability, induced apoptosis, and diminished tumor burden in RCC xenograft models. ELR510444 also destabilized microtubules suggesting that it possesses vascular disrupting and anti-angiogenic properties. Further investigation of ELR510444 for the therapy of RCC is warranted.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Carcinoma de Células Renales/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Neoplasias Renales/patología , Microtúbulos/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Sulfonamidas/farmacología , Tiofenos/farmacología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinoma de Células Renales/irrigación sanguínea , Carcinoma de Células Renales/metabolismo , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Renales/irrigación sanguínea , Neoplasias Renales/metabolismo , Ratones , Microtúbulos/metabolismo , Mitosis/efectos de los fármacos , Polimerizacion/efectos de los fármacos , Sulfonamidas/uso terapéutico , Tiofenos/uso terapéutico , Carga Tumoral/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inhibitors of hypoxia-inducible factor 1 (HIF-1) represent promising anticancer therapeutics. We have identified a series of potent toluidinesulfonamide HIF-1 inhibitors. However, the series was threatened by a potential liability to inhibit CYP2C9 which could cause dangerous drug-drug interactions when being coadministered with other drugs. We used structure-activity data from the PubChem database to develop a topomer CoMFA model that guided the design of novel sulfonamides with high selectivity for HIF-1 over CYP2C9 inhibition.