title: Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115.
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.
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Mortensen
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Perrin-Ninkovic
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Graziella
authors.initials: G
authors.lastname: Shevlin
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Jan
authors.initials: J
authors.lastname: Elsner
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Brandon
authors.initials: B
authors.lastname: Whitefield
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Lida
authors.initials: L
authors.lastname: Tehrani
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: John
authors.initials: J
authors.lastname: Sapienza
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Riggs
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Parnes
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Papa
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Garrick
authors.initials: G
authors.lastname: Packard
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Branden G S
authors.initials: BG
authors.lastname: Lee
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Roy
authors.initials: R
authors.lastname: Harris
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Correa
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Sogole
authors.initials: S
authors.lastname: Bahmanyar
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Richardson
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Sophie X
authors.initials: SX
authors.lastname: Peng
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Jim
authors.initials: J
authors.lastname: Leisten
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Godrej
authors.initials: G
authors.lastname: Khambatta
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Matt
authors.initials: M
authors.lastname: Hickman
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Gamez
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: René R
authors.initials: RR
authors.lastname: Bisonette
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Julius
authors.initials: J
authors.lastname: Apuy
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Cathers
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Stacie S
authors.initials: SS
authors.lastname: Canan
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Mehran F
authors.initials: MF
authors.lastname: Moghaddam
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Heather K
authors.initials: HK
authors.lastname: Raymon
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Worland
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Rama Krishna
authors.initials: RK
authors.lastname: Narla
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Fultz
authors.affiliation: Celgene Corporation, 10300 Campus Pointe Drive, Suite 100, San Diego, California 92121, United States.
authors.forename: Sabita
authors.initials: S
authors.lastname: Sankar
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011719:Pyrazines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D014230:Triazoles; D058570:TOR Serine-Threonine Kinases; C000601954:1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino(2,3-b)pyrazin-2(1H)-one