title: Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors.
abstract: Intra-molecular hydrogen bonding was introduced to the quinazoline motif to form a pseudo ring (intra-molecular H-bond scaffold, iMHBS) to mimic our previous published core structures, pyrido[2.3-D]pyrimidin-7-one and pteridinone, as PI3K/mTOR dual inhibitors. This design results in potent PI3K/mTOR dual inhibitors and the purposed intra-molecular hydrogen bonding structure is well supported by co-crystal structure in PI3Kγ enzyme. In addition, a novel synthetic route was developed for these analogs.
authors.affiliation: Pfizer Global Research and Development, Chemistry Department, 10770 Science Center Drive, La Jolla, CA 92120, USA. Kevin.K.Liu@pfizer.com
authors.forename: Kevin K C
authors.initials: KK
authors.lastname: Liu
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Huang
authors.forename: Shubha
authors.initials: S
authors.lastname: Bagrodia
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Chen
authors.forename: Samantha
authors.initials: S
authors.lastname: Greasley
authors.forename: Hengmiao
authors.initials: H
authors.lastname: Cheng
authors.forename: Shaoxian
authors.initials: S
authors.lastname: Sun
authors.forename: Dan
authors.initials: D
authors.lastname: Knighton
authors.forename: Caroline
authors.initials: C
authors.lastname: Rodgers
authors.forename: Kristina
authors.initials: K
authors.lastname: Rafidi
authors.forename: Aihua
authors.initials: A
authors.lastname: Zou
authors.forename: Jiezhan
authors.initials: J
authors.lastname: Xiao
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yan
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D058570:TOR Serine-Threonine Kinases