| References: |
CC-223 is a potent mTOR kinase inhibitor (IC50=16 nM), with >150-fold sensitivity over the related lipid kinase PI3Kα (IC50=4 μM).
in vitro: CC-223 is a potent, selective, and orally bioavailable inhibitor of mTOR kinase, demonstrating inhibition of mTORC1 (pS6RP and p4EBP1) and mTORC2 [pAKT(S473)] in cellular systems. CC-223 competitively inhibits the mTOR kinase that targets mTORC1 and mTORC2, prevents upregulation of AKT phosphorylation, differentiating it from the rapalogs.
in vivo: Treatment with CC-223 afforded in vivo tumor biomarker inhibition in tumor-bearing mice, after a single oral dose. CC-223 exhibited dose-dependent tumor growth inhibition in multiple solid tumor xenografts. CC-223 is active against many non-Hodgkin lymphoma cell lines and solid tumor lines, including breast, glioma, hepatocellular carcinoma (HCC), and non-small cell lung cancer. CC-223 has demonstrated single-agent activity in several human tumor xenograft models, including U87 glioblastoma multiforme and PC3 prostate cancer. CC-223 is tolerable, with manageable toxicities. CC-223, with superior physicochem-ical and pharmacokinetic properties, excellent kinase selectivity, demonstrates efficacy across multiple solid tumor models with oral dosing. |
