title: Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors.
abstract: We recently described several highly potent, triazine (1) and triazolopyrimidine (2) scaffold-based, dual PI3K/mTOR-inhibitors (e.g., 1, PKI-587) that were efficacious in both in vitro and in vivo models. In order to further optimize these compounds we devised a novel series, the 2-oxatriazines, which also exhibited excellent potency and good metabolic stability. Some 2-oxatriazines showed promising in vivo biomarker suppression and induced apoptosis in the MDA-MB-361 breast cancer xenograft model.
authors.affiliation: Medicinal Chemistry, Pfizer, 401 N. Middletown Rd., Pearl River, NY 10965, USA. christoph.dehnhardt@pfizer.com
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Dehnhardt
authors.forename: Aranapakam M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Zecheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Efren
authors.initials: E
authors.lastname: Delos-Santos
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Natasja
authors.initials: N
authors.lastname: Brooijmans
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
authors.forename: Irwin
authors.initials: I
authors.lastname: Hollander
authors.forename: Larry
authors.initials: L
authors.lastname: Feldberg
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Robert
authors.initials: R
authors.lastname: Mallon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D014227:Triazines; D058570:TOR Serine-Threonine Kinases