Abstract 4484: AR-mTOR-26 - A potent, selective mTORC 1/2 kinase inhibitor for the treatment of malignancy
Authors: Stefan D. Gross, Rui Xu, Mark Boys, Kevin Condroski, Lisa DeMeese, Walt E. DeWolf, Brad Fell, John Fischer, Susan Gloor, Michael J. Humphries, Greg Miknis, Kelly Regal, Mareli Rodriguez, Nicholas Raddatz, Kristin Shotts, Georg Topalov, Eli Wallace, John Zuzack, John A. Josey, James Winkler, Kevin Koch
Journal: Cancer Research (2010)

Abstract As a consequence of a variety of genetic lesions, the PI3K/Akt pathway is constitutively activated in a large proportion of human cancers. The mTOR kinase plays an important role in this pathway as the key component of two independent signaling complexes (TORC1 and TORC2) that are involved at two distinct levels in this signaling cascade. Accordingly, inhibition of mTOR kinase will abrogate signaling from both mTOR complexes and serve as an effective means of targeting this pathway. In addition, the activity of the TORC1 complex is often aberrantly activated in a PI3K-independent manner to allow tumor cells to survive and proliferate despite the many negative influences of the tumor microenvironment such as hypoxia and limited nutrient availability. Therefore, an inhibitor of both TORC1 and TORC2 should effectively block signaling from the PI3K pathway as well as abrogate the cancer cells’ ability to survive in the harsh environment of the tumor thereby providing an effective means of treating cancer. We report here the profile of our small molecule mTOR kinase inhibitor AR-mTOR-26. On enzyme, this compound inhibits mTOR kinase with an IC50 of 1 nM while exhibiting substantial selectivity against PI3Kα as well as a panel of lipid and protein kinases. In cells, AR-mTOR-26 inhibits the TORC1-dependent readouts pS6 (Ser235/6) and p4E-BP1 (Ser37/46) as well as the TORC2 phosphorylation site on Akt, Ser473, with IC50 values of &amp;lt;50 nM. Consistent with its selectivity over PI3Kα, AR-mTOR-26 does not significantly inhibit Thr308 on AKT, a PI3K/PDK1-dependent readout. In addition, we show that AR-mTOR-26 is broadly and potently anti-proliferative across a panel of solid and hematological cancer cell lines, irrespective of their mutational status suggesting the potential for broad therapeutic utility. We then evaluated the in vivo activity of AR-mTOR-26. By oral administration, AR-mTOR-26 exhibits excellent pharmacokinetics in mice with plasma concentrations that are predicted to be efficacious. Doses ranging from 1-10 mg/kg once daily to tumor-bearing mice results in significant anti-tumor activity in several mouse xenograft models, including PC3 prostate [PTEN null] and H460 lung [KRASG12D/PIK3CA]. These effects ranged from tumor growth inhibition to regressions dependent upon the dose and the xenograft model evaluated. In all, these data show that targeting mTOR kinase with AR-mTOR-26 holds promise as a broadly acting therapeutic for oncology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4484.