Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115.
Basic Information
ID: ALA3585264
Journal: J Med Chem
Title: Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115.
Authors: Mortensen DS, Perrin-Ninkovic SM, Shevlin G, Elsner J, Zhao J, Whitefield B, Tehrani L, Sapienza J, Riggs JR, Parnes JS, Papa P, Packard G, Lee BG, Harris R, Correa M, Bahmanyar S, Richardson SJ, Peng SX, Leisten J, Khambatta G, Hickman M, Gamez JC, Bisonette RR, Apuy J, Cathers BE, Canan SS, Moghaddam MF, Raymon HK, Worland P, Narla RK, Fultz KE, Sankar S.
Abstract: We report here the synthesis and structure-activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy in tumor xenograft models. This work resulted in the selection of CC-115 for clinical development.
CiteXplore: 26102506
DOI: 10.1021/acs.jmedchem.5b00627
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