title: Use of core modification in the discovery of CC214-2, an orally available, selective inhibitor of mTOR kinase.
abstract: We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model. A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were discovered through a core modification of our original compound series. Analogs from this series have excellent mTOR potency and maintain selectivity over the related PI3Kα lipid kinase. Compounds such as CC214-2 were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC3 cancer cells, in vitro and in vivo.
authors: Department of Medicinal Chemistry, Celgene Corporation, 4550 Towne Centre Court, San Diego, CA 92121, United States. dmortens@celgene.com
authors: Deborah S
authors: DS
authors: Mortensen
authors: John
authors: J
authors: Sapienza
authors: Branden G S
authors: BG
authors: Lee
authors: Sophie M
authors: SM
authors: Perrin-Ninkovic
authors: Roy
authors: R
authors: Harris
authors: Graziella
authors: G
authors: Shevlin
authors: Jason S
authors: JS
authors: Parnes
authors: Brandon
authors: B
authors: Whitefield
authors: Matt
authors: M
authors: Hickman
authors: Gody
authors: G
authors: Khambatta
authors: Rene R
authors: RR
authors: Bisonette
authors: Sophie
authors: S
authors: Peng
authors: Jim C
authors: JC
authors: Gamez
authors: Jim
authors: J
authors: Leisten
authors: Rama Krishna
authors: RK
authors: Narla
authors: Kimberly E
authors: KE
authors: Fultz
authors: Sabita
authors: S
authors: Sankar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D058570:TOR Serine-Threonine Kinases; C583190:CC214-2; C546842:MTOR protein, human