title: 4-methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors.
abstract: Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.
authors.affiliation: Pfizer Global Research and Development, Chemistry Department, La Jolla, CA 92120, USA. kevin.k.liu@pfizer.com
authors.forename: Kevin K-C
authors.initials: KK
authors.lastname: Liu
authors.forename: Shubha
authors.initials: S
authors.lastname: Bagrodia
authors.forename: Simon
authors.initials: S
authors.lastname: Bailey
authors.forename: Hengmiao
authors.initials: H
authors.lastname: Cheng
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Lisa
authors.initials: L
authors.lastname: Gao
authors.forename: Samantha
authors.initials: S
authors.lastname: Greasley
authors.forename: Jacqui E
authors.initials: JE
authors.lastname: Hoffman
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Hu
authors.forename: Ted O
authors.initials: TO
authors.lastname: Johnson
authors.forename: Dan
authors.initials: D
authors.lastname: Knighton
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Liu
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Marx
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Nambu
authors.forename: Sacha
authors.initials: S
authors.lastname: Ninkovic
authors.forename: Bernadette
authors.initials: B
authors.lastname: Pascual
authors.forename: Kristina
authors.initials: K
authors.lastname: Rafidi
authors.forename: Caroline M-L
authors.initials: CM
authors.lastname: Rodgers
authors.forename: Graham L
authors.initials: GL
authors.lastname: Smith
authors.forename: Shaoxian
authors.initials: S
authors.lastname: Sun
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.forename: Anle
authors.initials: A
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Aihua
authors.initials: A
authors.lastname: Zou
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005910:Glioma / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011621:Pteridines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D012995:Solubility; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011621:Pteridines; D058570:TOR Serine-Threonine Kinases