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CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization
- Source :
- Molecular Cancer Therapeutics. 14:1295-1305
- Publication Year :
- 2015
- Publisher :
- American Association for Cancer Research (AACR), 2015.
-
Abstract
- mTOR is a serine/threonine kinase that regulates cell growth, metabolism, proliferation, and survival. mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2) are critical mediators of the PI3K–AKT pathway, which is frequently mutated in many cancers, leading to hyperactivation of mTOR signaling. Although rapamycin analogues, allosteric inhibitors that target only the mTORC1 complex, have shown some clinical activity, it is hypothesized that mTOR kinase inhibitors, blocking both mTORC1 and mTORC2 signaling, will have expanded therapeutic potential. Here, we describe the preclinical characterization of CC-223. 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. Growth inhibitory activity was demonstrated in hematologic and solid tumor cell lines. mTOR kinase inhibition in cells, by CC-223, resulted in more complete inhibition of the mTOR pathway biomarkers and improved antiproliferative activity as compared with rapamycin. Growth inhibitory activity and apoptosis was demonstrated in a panel of hematologic cancer cell lines. Correlative analysis revealed that IRF4 expression level associates with resistance, whereas mTOR pathway activation seems to associate with sensitivity. 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. Significant inhibition of mTOR pathway markers pS6RP and pAKT in CC-223–treated tumors suggests that the observed antitumor activity of CC-223 was mediated through inhibition of both mTORC1 and mTORC2. CC-223 is currently in phase I clinical trials. Mol Cancer Ther; 14(6); 1295–305. ©2015 AACR.
- Subjects :
- Cancer Research
Blotting, Western
Apoptosis
P70-S6 Kinase 1
Mechanistic Target of Rapamycin Complex 2
Mice, SCID
mTORC1
Mechanistic Target of Rapamycin Complex 1
Biology
mTORC2
In vivo
Cell Line, Tumor
Neoplasms
Animals
Humans
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Cell Proliferation
Dose-Response Relationship, Drug
Molecular Structure
Neovascularization, Pathologic
Cell growth
Kinase
TOR Serine-Threonine Kinases
RPTOR
HCT116 Cells
Xenograft Model Antitumor Assays
Tumor Burden
HEK293 Cells
Oncology
Multiprotein Complexes
Pyrazines
Cancer research
Female
Subjects
Details
- ISSN :
- 15388514 and 15357163
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer Therapeutics
- Accession number :
- edsair.doi.dedup.....50876b20cd6236c0e871976f53e0b444