2. Academic Validation
  3. Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115

Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115

  • J Med Chem. 2015 Jul 23;58(14):5599-608. doi: 10.1021/acs.jmedchem.5b00627.
Deborah S Mortensen 1,  Sophie M Perrin-Ninkovic 1,  Graziella Shevlin 1,  Jan Elsner 1,  Jingjing Zhao 1,  Brandon Whitefield 1,  Lida Tehrani 1,  John Sapienza 1,  Jennifer R Riggs 1,  Jason S Parnes 1,  Patrick Papa 1,  Garrick Packard 1,  Branden G S Lee 1,  Roy Harris 1,  Matthew Correa 1,  Sogole Bahmanyar 1,  Samantha J Richardson 1,  Sophie X Peng 1,  Jim Leisten 1,  Godrej Khambatta 1,  Matt Hickman 1,  James C Gamez 1,  René R Bisonette 1,  Julius Apuy 1,  Brian E Cathers 1,  Stacie S Canan 1,  Mehran F Moghaddam 1,  Heather K Raymon 1,  Peter Worland 1,  Rama Krishna Narla 1,  Kimberly E Fultz 1,  Sabita Sankar 1
Affiliations

Affiliation

  • 1 Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
PMID: 26102506 DOI: 10.1021/acs.jmedchem.5b00627
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.

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