Use of core modification in the discovery of CC214-2, an orally available, selective inhibitor of mTOR kinase

We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model. A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-one...

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Published in:	Bioorganic & medicinal chemistry letters Vol. 23; no. 6; pp. 1588 - 1591
Main Authors:	Mortensen, Deborah S., Sapienza, John, Lee, Branden G.S., Perrin-Ninkovic, Sophie M., Harris, Roy, Shevlin, Graziella, Parnes, Jason S., Whitefield, Brandon, Hickman, Matt, Khambatta, Gody, Bisonette, Rene R., Peng, Sophie, Gamez, Jim C., Leisten, Jim, Narla, Rama Krishna, Fultz, Kimberly E., Sankar, Sabita
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 15-03-2013
Subjects:	Administration, Oral Animals anticarcinogenic activity Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Cell Line, Tumor Cell Proliferation - drug effects chemistry Drug Evaluation, Preclinical Half-Life Humans Kinase inhibitors Male Mammalian target of rapamycin Mice mTOR kinase Oncology Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism PI3K/Akt/mTOR pathway prostatic neoplasms Prostatic Neoplasms - drug therapy Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - therapeutic use Proto-Oncogene Proteins c-akt - metabolism Pyrazines - chemistry Pyrazines - pharmacokinetics Pyrazines - therapeutic use Pyrazines - toxicity Signal Transduction - drug effects TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - metabolism Transplantation, Heterologous mTOR kinase Oncology Kinase inhibitors PI3K/Akt/mTOR pathway Mammalian target of rapamycin
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Summary:	We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model. A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were discovered through a core modification of our original compound series. Analogs from this series have excellent mTOR potency and maintain selectivity over the related PI3Kα lipid kinase. Compounds such as CC214-2 were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC3 cancer cells, in vitro and in vivo.
Bibliography:	http://dx.doi.org/10.1016/j.bmcl.2013.01.110 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.01.110