VQD 002, a water Sliches tricyclic nucleotide is currently in phase I clinical trials in patients with solid and tested h Dermatological malignancies. It was reported BMS-582664 Brivanib alaninate recently that TCN P k Nnte An r Reversal play in the resistance in ovarian cancer patients , but its mechanism of action is unclear. Although mTOR targeting mTOR has recently been defined as a member of PI3K, it is the first node in the path aligned to the clinic. Rapamycin, mTOR inhibitor prototype is a natural product of bacterial originally antifungal agent78and sp Ter immunosuppressive79and have recently used anti-cancer properties. Rapamycin and its intracellular Ren receptor FK506 binding protein 12, which binds to and directly suppresses mTORC1 mTOR mediated phosphorylation of its downstream Rtigen substrates and connected 4EBP12180 S6K.
Rapamycin analogues such as CCI 779, RAD001 and AP23573 were developed as anti-cancer drugs. These analogs of rapamycin, which are sometimes as rapalogs., MTOR inhibition by the same mechanism as rapamycin, but better pharmacological properties for clinical use in cancer therapy Many studies mTOR inhibitor in cancer therapy have been described. AP23573 is approved for the treatment of bone and soft tissue sarcomas. Encouraging results of recent clinical studies with ICC 779 and RAD001 as monotherapy showed that mTOR drugs improved survival rate in patients with advanced renal cell carcinoma, which to their clinical approval in this indication, 80, 83 However vorl gave INDICATIVE results with mTOR inhibitors in many other tumor types, including normal advanced breast cancer and glioma, a low response rate betr Gt 80th Especially mTOR is also a potential target on his second mTORC2 complex phosphorylates a burden PDK2 the carboxy of AKT at Ser473, a mandatory event required activation 18 vervollst Ndigen acts.
Although the clinical significance of PDK2 function in cancer is unknown, a recent study showed that mTORC2 is induced in the development of prostate tumors by loss of PTEN 84 required. Thus, an inhibitor of mTOR kinase in a position to the expected both mTORC2 mTORC1 and that activation of PI3K block effective than rapamycin. Some recent studies have potent and selective ATP competitive inhibitors of mTOR and TORKinibs Torin1 which inhibit both mTORC1 and mTORC2 complexes and influence the growth and proliferation better than rapamycin85 reported, 86.
Interestingly, however, the increased Hte activity Made of mTOR kinase inhibitors t by mTORC2 inhibition, and seems t satisfied by inhibiting the activity of t MTORC1 completely Ndigere as-dependent dependent by mTORC1 And independent-Dependent 4E BP1 phosphorylation rapamycin measured be dependent translation85 dependent and cap, 86 Two ATP-competitive mTOR inhibitors, AZD8055 027 and the OSI are currently in clinical trials in patients with solid tumors and lymphomas, it is also interesting to note that several kinases in the PI3K signaling pathway client proteins Are the heat shock protein 90 8788th So K may compounds that inhibit the protein Hsp90, as geldanamycin and its analogs therapeutic effects, at least partially have the inhibition of PI3K.