title: Discovery and SAR exploration of a novel series of imidazo[4,5-b]pyrazin-2-ones as potent and selective mTOR kinase inhibitors.
abstract: We report here the discovery of a novel series of selective mTOR kinase inhibitors. A series of imidazo[4,5-b]pyrazin-2-ones, represented by screening hit 1, was developed into lead compounds with excellent mTOR potency and exquisite kinase selectivity. Potent compounds from this series show >1000-fold selectivity over the related PI3Kα lipid kinase. Further, compounds such as 2 achieve mTOR pathway inhibition, blocking both mTORC1 and mTORC2 signaling, in PC3 cancer cells as measured by inhibition of pS6 and pAkt (S473).
authors: Medicinal Chemistry, Celgene Corporation, 4550 Towne Centre Court, San Diego, CA 92121, USA. dmortens@celgene.com
authors: Deborah S
authors: DS
authors: Mortensen
authors: Sophie M
authors: SM
authors: Perrin-Ninkovic
authors: Roy
authors: R
authors: Harris
authors: Branden G S
authors: BG
authors: Lee
authors: Graziella
authors: G
authors: Shevlin
authors: Matt
authors: M
authors: Hickman
authors: Gody
authors: G
authors: Khambatta
authors: Rene R
authors: RR
authors: Bisonette
authors: Kimberly E
authors: KE
authors: Fultz
authors: Sabita
authors: S
authors: Sankar
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D058570:TOR Serine-Threonine Kinases