The mammalian target of rapamycin (mTOR) integrates signals from growth factors, nutrients and amino acids to regulate, translation, cell growth and proliferation. mTOR is present in two multi-protein complexes, a rapamycin sensitive complex, mTORC1, defined by the presence of Raptor and a rapamycin insensitive complex, mTORC2, with Rictor, Protor and Sin1. Rapamycin selectively inhibits mTORC1 because it binds indirectly to the mTOR/Raptor complex via FKBP12, this results in inhibition of p70S6kinase but not the mTORC2 substrate AKTSer473. Selective inhibition of p70S6K attenuates negative feedback loops to IRS1 and TORC2 resulting in an increase in pAKT which may limit the activity of Rapamycin. We reasoned that direct inhibition of the catalytic activity of mTOR would inhibit both mTORC1 and mTORC2 resulting in a more profound and different spectrum of activity compared to Rapamycin. AZD8055 is a small molecule inhibitor that competes with ATP for binding to mTOR, thus inhibiting both mTORC1 and mTORC2. mTOR is potently and selectively inhibited by AZD8055 with an IC50 of less than 1nM in an in vitro mTOR kinase assay (IC50 0.13 ± 0.05 nM using recombinant mTOR), and IC50s of greater than 1\#956;M for other PI3kinases (PI3K\#945;, \#946;, \#948; and \#947;) and PI3kinase-like kinases (ATM and DNA-PK), furthermore there was no inhibition of >200 non-PIKK kinases at 10\#956;M. Treatment of a broad range of tumour cell lines with AZD8055 for 2h results in potent inhibition of both mTORC1 (p70S6KThr389) and mTORC2 substrates (pAKTSer473) and downstream signalling cascades. Significantly, AZD8055 inhibits p4EBP1 Thr37/46 in cells where this site is rapamycin resistant suggesting a differential effect on TORC1 substrates. Studies of large cell panels (>100 lines) indicates the anti-proliferative activity of AZD8055 was more profound than that of Rapamycin, resulting in more complete growth inhibition and cell death in some cell types. Chronic dosing of up to 20 mg/kg qd AZD8055 was well tolerated, and resulted in a dose-dependent inhibition of growth of U87-MG xenografts. Analysis of pharmacodynamic markers indicated both TORC1 and TORC2 complexes were inhibited in vivo.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4770.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO