Through alterations in the PTEN and PI3K genes, the PI3K / Akt pathway is constitutively activated in human cancers. mTOR kinase plays an unique role in this pathway as the key component of two independent signaling complexes (mTORC1 (raptor ‐ rapamycin sensitive) and mTORC2 (rictor ‐ rapamycin insensitive)) that are involved at multiple branch points in this signaling cascade. As such, inhibition of mTOR kinase inactivates both mTOR complexes and therefore serves as an attractive means to target this integral pathway for the treatment of human malignancy.
We report the biological and pharmaceutical evaluation of our selective mTOR 1/2 kinase inhibitor AR‐mTOR‐1. AR‐mTOR‐1 inhibits mTOR kinase with an IC50 of < 10 nM while maintaining selectivity against PI3K as well as a panel of additional lipid kinases, serine/threonine kinases and cytoplasmic and receptor tyrosine kinases. In mechanistic cellular assays, AR‐mTOR‐1 inhibits pAkt (Ser473), 4E‐BP1 (Thr36/46) and pS6 (Ser235/6) with nanomolar potency, thus demonstrating inhibition of signaling from both mTORC1 and mTORC2 complexes. In line with its enzymatic selectivity over PI3K , AR‐mTOR‐1 does not significantly inhibit pAkt (Thr308) in cells. AR‐mTOR‐1 is broadly anti‐proliferative in both epithelial and hematologic cancer cell lines, irrespective of mutational status, with IC50's ranging from 30 to 550 nM across 20 cell lines, suggesting the potential for broad clinical activity. Once daily dosing of AR‐mTOR‐1 in several mouse xenograft models, including PC3 prostate, U87 glioblastma, and H460 lung, results in robust anti‐tumor activity. Finally, AR‐mTOR‐1 possesses desired in vitro and in vivo preclinical ADME properties including low clearance, high permeability and good absorption in three preclinical species. In total these data demonstrate that selectively targeting mTORC1 and mTORC2 with AR‐mTOR‐1 holds promise for broad spectrum clinical utility as a single agent across a wide array of cancer types.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B267.