title: Structure-based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4-methylpyridopyrimidinone series.
abstract: PI3K, AKT and mTOR, key kinases from a frequently dysregulated PI3K signaling pathway, have been extensively pursued to treat a variety of cancers in oncology. Clinical trials of PF-04691502, a highly potent and selective ATP competitive kinase inhibitor of class 1 PI3Ks and mTOR, from 4-methylpyridopyrimidinone series, led to the discovery of a metabolite with a terminal carboxylic acid, PF-06465603. This paper discusses structure-based drug design, SAR and antitumor activity of the MPP derivatives with a terminal alcohol, a carboxylic acid or a carboxyl amide.
authors.affiliation: Cancer Chemistry, Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA. henry.cheng@pfizer.com
authors.forename: Hengmiao
authors.initials: H
authors.lastname: Cheng
authors.forename: Jacqui E
authors.initials: JE
authors.lastname: Hoffman
authors.forename: Phuong T
authors.initials: PT
authors.lastname: Le
authors.forename: Mason
authors.initials: M
authors.lastname: Pairish
authors.forename: Robert
authors.initials: R
authors.lastname: Kania
authors.forename: William
authors.initials: W
authors.lastname: Farrell
authors.forename: Shubha
authors.initials: S
authors.lastname: Bagrodia
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Shaoxian
authors.initials: S
authors.lastname: Sun
authors.forename: Eric
authors.initials: E
authors.lastname: Zhang
authors.forename: Cathy
authors.initials: C
authors.lastname: Xiang
authors.forename: Deepak
authors.initials: D
authors.lastname: Dalvie
authors.forename: Sadayappan V
authors.initials: SV
authors.lastname: Rahavendran
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D011743:Pyrimidines; D011744:Pyrimidinones; D058570:TOR Serine-Threonine Kinases; C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one