| Literature DB >> 26102506 |
Deborah S Mortensen1, Sophie M Perrin-Ninkovic1, Graziella Shevlin1, Jan Elsner1, Jingjing Zhao1, Brandon Whitefield1, Lida Tehrani1, John Sapienza1, Jennifer R Riggs1, Jason S Parnes1, Patrick Papa1, Garrick Packard1, Branden G S Lee1, Roy Harris1, Matthew Correa1, Sogole Bahmanyar1, Samantha J Richardson1, Sophie X Peng1, Jim Leisten1, Godrej Khambatta1, Matt Hickman1, James C Gamez1, René R Bisonette1, Julius Apuy1, Brian E Cathers1, Stacie S Canan1, Mehran F Moghaddam1, Heather K Raymon1, Peter Worland1, Rama Krishna Narla1, Kimberly E Fultz1, Sabita Sankar1.
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.Entities:
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Year: 2015 PMID： 26102506 DOI： 10.1021/acs.jmedchem.5b00627
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446