Ku-0063794 is a specific ATP-competitive mTOR inhibitor blocking mTORC1 and mTORC2.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | In vitro; cells |
| Journal | The Biochemical journal |
| Year | 2009 |
| Peer reviewed | Yes |
| Source | DOI 10.1042/BJ20090489 · PMID 19402821 · Free full text (PMC2708931) |
mTOR (mammalian target of rapamycin) stimulates cell growth by phosphorylating and promoting activation of AGC 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, whereas mTORC2 phosphorylates the hydrophobic motif of Akt and SGK. In the present paper we describe the small molecule Ku-0063794, which inhibits both mTORC1 and mTORC2 with an IC50 of approximately 10 nM, but does not suppress the activity of 76 other protein kinases or seven lipid kinases, including Class 1 PI3Ks at 1000-fold higher concentrations. Ku-0063794 is cell permeant, suppresses activation and hydrophobic motif phosphorylation of Akt, S6K and SGK, but not RSK, an AGC kinase not regulated by mTOR. Ku-0063794 also inhibited phosphorylation of the T-loop Thr308 residue of Akt phosphorylated by PDK1. In contrast, Ku-0063794 does not affect Thr308 phosphorylation in fibroblasts lacking essential mTORC2 subunits, suggesting that signalling processes have adapted to enable Thr308 phosphorylation to occur in the absence of Ser473 phosphorylation. We found that Ku-0063794 induced a much greater dephosphorylation of the mTORC1 substrate 4E-BP1 than rapamycin, even in mTORC2-deficient cells. Ku-0063794 also suppressed cell growth and induced a G1-cell-cycle arrest. Our results indicate that Ku-0063794 will be useful in delineating the physiological roles of mTOR and may have utility in treatment of cancers in which this pathway is inappropriately activated.
| Intervention | Ku-0063794 (ATP-competitive mTOR inhibitor) |
| Target | mTORC1 & mTORC2 |
| Model | In vitro; cells |
| Effect | Ku-0063794 is a specific mTOR inhibitor blocking both complexes (Akt/S6K/SGK signaling) |