title: Design, synthesis, and biological activity of pyridopyrimidine scaffolds as novel PI3K/mTOR dual inhibitors.
abstract: The design, synthesis, and screening of dual PI3K/mTOR inhibitors that gave nanomolar enzymatic and cellular activities on both targets with an acceptable kinase selectivity profile are described. A docking study was performed to understand the binding mode of the compounds and to explain the differences in biological activity. In addition, cellular effects of the best dual inhibitors were determined on six cancer cell lines and compared to those on a healthy diploid cell line for cellular cytotoxicity. Two compounds are highly potent on cancer cells in the submicromolar range without any toxicity on healthy cells. A more detailed analysis of the cellular effect of these PI3K/mTOR dual inhibitors demonstrated that they induce G1-phase cell cycle arrest in breast cancer cells and trigger apoptosis. These compounds show an interesting kinase profile as dual PI3K/mTOR tool compounds or as a chemical series for further optimization to progress into in vivo experiments.
authors.affiliation: Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311 , Rue de Chartres, BP 6759, 45067 OrléansCedex 2, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Saurat
authors.forename: Frédéric
authors.initials: F
authors.lastname: Buron
authors.forename: Nuno
authors.initials: N
authors.lastname: Rodrigues
authors.forename: Marie-Ludivine
authors.initials: ML
authors.lastname: de Tauzia
authors.forename: Lionel
authors.initials: L
authors.lastname: Colliandre
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bourg
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnet
authors.forename: Gérald
authors.initials: G
authors.lastname: Guillaumet
authors.forename: Mohamed
authors.initials: M
authors.lastname: Akssira
authors.forename: Anne
authors.initials: A
authors.lastname: Corlu
authors.forename: Christiane
authors.initials: C
authors.lastname: Guillouzo
authors.forename: Pauline
authors.initials: P
authors.lastname: Berthier
authors.forename: Pascale
authors.initials: P
authors.lastname: Rio
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Jourdan
authors.forename: Hélène
authors.initials: H
authors.lastname: Bénédetti
authors.forename: Sylvain
authors.initials: S
authors.lastname: Routier
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D062105:Molecular Docking Simulation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases