title: Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223.
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.
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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C000601736:CC-223; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D058570:TOR Serine-Threonine Kinases