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The mTOR (mammalian target of rapamycin) protein kinase lies at the nexus of signaling pathways that regulate cell growth and proliferation. Various cancer-driving mutations in genes such as receptor tyrosine kinases, Ras, PI3K (phosphoinositide 3-kinase) and PTEN (phosphatase and tensin homologue deleted on chromosome 10) stimulate proliferation, growth and survival by the activation of mTOR kinase. MTOR stimulates cell growth by phosphorylating and promoting activation of AGC (protein kinase A/protein kinase G/protein kinase C) family kinases such as Akt (protein kinase B), S6K (p70 ribosomal S6 kinase) and SGK(serum and glucocorticoid protein kinase). MTORC1 phosphorylates the hydrophobic motif of S6K, while mTORC2 phosphorylates the hydrophobic motif of Akt and SGK. Ku-0063794 inhibits both mTORC1 and mTORC2 in vitro and in vivo and can be used to dissect cellular functions of the mTOR pathway.[1]

In HEK-293 cells, Ku-0063794 inhibited the activity of endogenous immunoprecipitated mTORC1 and mTORC2, employing S6K1 and Akt as substrates, with IC50 values of ~10nM. The ability of Ku-0063794 to suppress S6K1 activity and phosphorylation was rapid,Concentrations

of 100–300 nM Ku-0063794 were required to fully suppress amino-acid-induced phosphorylation of S6K1 and S6 protein. Ku-0063794 inhibits phosphorylation of Akt at Thr 308. Ku-0063794 was also assessed for other targets. However, it does not significantly inhibit 76 other protein kinases tested as well as seven lipid kinases, including class 1a PI3K α and PI3K β.[1,2]

The antileukemic effects of Ku-0063794 of the PI3K signaling pathway were evaluated by methylcellulose colony assays with primary murine CML cells obtained from mice that underwent bone marrow reconstitution with hematopoietic cells transduced with a retrovirus vector-expressing BCR/ABL. It showed that Ku-0063794 fully suppressed colony formation of primary murine CML at 1000nM. Moreover, KU-0063794 strikingly reduces cell proliferation in BA/F3 cells expressing BCR/ABL independently of mutation status, which indicates Ku-0063794 is a desirable therapeutic strategy to affect oncogenes signaling downstream of BCR/ABL.[2]

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