title: CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization.
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.
authors: Celgene Corporation, San Diego, California. dmortens@celgene.com.
authors: Deborah S
authors: DS
authors: Mortensen
authors: Celgene Corporation, San Diego, California.
authors: Kimberly E
authors: KE
authors: Fultz
authors: Celgene Corporation, San Diego, California.
authors: Shuichan
authors: S
authors: Xu
authors: Celgene Corporation, San Diego, California.
authors: Weiming
authors: W
authors: Xu
authors: Celgene Corporation, San Diego, California.
authors: Garrick
authors: G
authors: Packard
authors: Celgene Corporation, San Diego, California.
authors: Godrej
authors: G
authors: Khambatta
authors: Celgene Corporation, San Diego, California.
authors: James C
authors: JC
authors: Gamez
authors: Celgene Corporation, San Diego, California.
authors: Jim
authors: J
authors: Leisten
authors: Celgene Corporation, San Diego, California.
authors: Jingjing
authors: J
authors: Zhao
authors: Celgene Corporation, San Diego, California.
authors: Julius
authors: J
authors: Apuy
authors: Celgene Corporation, San Diego, California.
authors: Kamran
authors: K
authors: Ghoreishi
authors: Celgene Corporation, San Diego, California.
authors: Matt
authors: M
authors: Hickman
authors: Celgene Corporation, San Diego, California.
authors: Rama Krishna
authors: RK
authors: Narla
authors: Celgene Corporation, San Diego, California.
authors: Rene
authors: R
authors: Bissonette
authors: Celgene Corporation, San Diego, California.
authors: Samantha
authors: S
authors: Richardson
authors: Celgene Corporation, San Diego, California.
authors: Sophie X
authors: SX
authors: Peng
authors: Celgene Corporation, San Diego, California.
authors: Sophie
authors: S
authors: Perrin-Ninkovic
authors: Celgene Corporation, San Diego, California.
authors: Tam
authors: T
authors: Tran
authors: Celgene Corporation, San Diego, California.
authors: Tao
authors: T
authors: Shi
authors: Celgene Corporation, San Diego, California.
authors: Wen Qing
authors: WQ
authors: Yang
authors: Celgene Corporation, Summit, New Jersey.
authors: Zeen
authors: Z
authors: Tong
authors: Celgene Corporation, San Diego, California.
authors: Brian E
authors: BE
authors: Cathers
authors: Celgene Corporation, San Diego, California.
authors: Mehran F
authors: MF
authors: Moghaddam
authors: Celgene Corporation, San Diego, California.
authors: Stacie S
authors: SS
authors: Canan
authors: Celgene Corporation, San Diego, California.
authors: Peter
authors: P
authors: Worland
authors: Celgene Corporation, San Diego, California.
authors: Sabita
authors: S
authors: Sankar
authors: Celgene Corporation, San Diego, California.
authors: Heather K
authors: HK
authors: Raymon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D016513:Mice, SCID; D015394:Molecular Structure; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000601736:CC-223; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases