Various analogs with substituents at the p position of the phenyl rin

ovatodiolide is a potent inhibitor of catenin signaling and therefore inhibits cell viability, migration, invasion, and both in vitro and in vivo tumorigenicity of RCC but induces less cytotoxicity in normal kidney cells. Ovatodiolide had synergistic effects with sorafenib or sunitinib and enhanced the combined treatment Ibrutinib response. Ovatodiolide may be a promising candidate for RCC treatment. Transcription factor FoxO1 promotes hepatic glucose production. Genetic inhibition of FoxO1 function prevents diabetes in experimental animal models, providing impetus to identify pharmacological approaches to modulate its function. Altered Notch signaling is seen in tumorigenesis, and Notch antagonists are in clinical testing for cancer application. Here, we report that FoxO1 and Notch coordinately regulate hepatic glucose metabolism. Combined haploinsufficiency of FoxO1 and Notch1 markedly improves insulin sensitivity in diet induced insulin resistance, as does liver specific knockout of the Notch transcriptional effector, Rbp Jk. Conversely, Notch1 gain of function promotes insulin Metastasis resistance in a FoxO1 dependent manner and induces Glucose 6 phosphatase expression. Pharmacological blockade of Notch signaling with secretase inhibitors improves insulin sensitivity following in vivo administration in lean and in obese, insulin resistant mice. The data identify a heretofore unknown metabolic function of Notch, and suggest that Notch inhibition is beneficial to diabetes treatment, in part by helping to offset excessive FoxO1?driven hepatic glucose production. Type 2 diabetes is associated with obesity and insulin resistance1. The pathophysiology of the insulin?resistant state remains enigmatic, and currently available insulin sensitizers are only partially effective at improving glucose disposal in skeletal muscle and suppressing hepatic gluconeogenesis2. Lonafarnib A more detailed knowledge of pathways that influence insulin resistance is necessary to identify new targets for the development of anti diabetic drugs3. Forkhead box containing transcription factors of the FoxO subfamily are key effectors of insulin action in metabolic processes, including hepatic glucose production 4. Hepatic FoxO1 promotes transcription of glucose 6 phosphatase and phosphoenolpyruvate carboxykinase, the rate limiting enzymes in hepatic glycogenolysis and gluconeogenesis, respectively5. FoxO1 is phosphorylated by Akt, leading to its nuclear exclusion and degradation6. In insulin resistance, FoxO1 is constitutively active, leading to increased HGP and fasting hyperglycemia7. Despite the importance of FoxO1 in regulation of hepatic insulin sensitivity8, it remains a poor candidate as a drug target due to the lack of a ligand binding domain and broad transcriptional signature.