RESUMO
Cancer cells sustain growth by altering their metabolism to accelerated aerobic glycolysis accompanied by increased glucose demand and employ glutamine as additional nutrient source. This metabolic adaptation induces upregulation of glucose transporters GLUT-1 and -3, and simultaneous targeting of both transporters and of glutamine metabolism may offer a promising approach to inhibit cancer cell growth. We describe the discovery of the very potent glucose uptake inhibitor Glutor, which targets glucose transporters GLUT-1, -2, and -3, attenuates glycolytic flux and potently and selectively suppresses growth of a variety of cancer cell lines. Co-treatment of colon cancer cells with Glutor and glutaminase inhibitor CB-839 very potently and synergistically inhibits cancer cell growth. Such a dual inhibition promises to be particularly effective because it targets the metabolic plasticity as well as metabolic rescue mechanisms in cancer cells.
Assuntos
Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glutaminase/metabolismo , Benzenoacetamidas/farmacologia , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo do Ácido Cítrico , Feminino , Glucose/metabolismo , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 3/antagonistas & inibidores , Transportador de Glucose Tipo 3/metabolismo , Glutaminase/antagonistas & inibidores , Glutamina/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Masculino , Neoplasias/metabolismo , Tiadiazóis/farmacologiaRESUMO
Natural products (NPs) inspire the design and synthesis of novel biologically relevant chemical matter, for instance through biology-oriented synthesis (BIOS). However, BIOS is limited by the partial coverage of NP-like chemical space by the guiding NPs. The design and synthesis of "pseudo NPs" overcomes these limitations by combining NP-inspired strategies with fragment-based compound design through deâ novo combination of NP-derived fragments to unprecedented compound classes not accessible through biosynthesis. We describe the development and biological evaluation of pyrano-furo-pyridone (PFP) pseudo NPs, which combine pyridone- and dihydropyran NP fragments in three isomeric arrangements. Cheminformatic analysis indicates that the PFPs reside in an area of NP-like chemical space not covered by existing NPs but rather by drugs and related compounds. Phenotypic profiling in a target-agnostic "cell painting" assay revealed that PFPs induce formation of reactive oxygen species and are structurally novel inhibitors of mitochondrial complexâ I.
