Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223

  • J Med Chem. 2015 Jul 9;58(13):5323-33. doi: 10.1021/acs.jmedchem.5b00626.
Deborah S Mortensen  1 ,  Sophie M Perrin-Ninkovic  1 ,  Graziella Shevlin  1 ,  Jingjing Zhao  1 ,  Garrick Packard  1 ,  Sogole Bahmanyar  1 ,  Matthew Correa  1 ,  Jan Elsner  1 ,  Roy Harris  1 ,  Branden G S Lee  1 ,  Patrick Papa  1 ,  Jason S Parnes  1 ,  Jennifer R Riggs  1 ,  John Sapienza  1 ,  Lida Tehrani  1 ,  Brandon Whitefield  1 ,  Julius Apuy  1 ,  René R Bisonette  1 ,  James C Gamez  1 ,  Matt Hickman  1 ,  Godrej Khambatta  1 ,  Jim Leisten  1 ,  Sophie X Peng  1 ,  Samantha J Richardson  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
  • 1. Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
PMID: 26083478 DOI: 10.1021/acs.jmedchem.5b00626
Abstract

We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.