title: 5-(2-amino-pyrimidin-4-yl)-1H-pyrrole and 2-(2-amino-pyrimidin-4-yl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one derivatives as new classes of selective and orally available Polo-like kinase 1 inhibitors.
abstract: The discovery and characterization of two new chemical classes of potent and selective Polo-like kinase 1 (PLK1) inhibitors is reported. For the most interesting compounds, we discuss the biological activities, crystal structures and preliminary pharmacokinetic parameters. The more advanced compounds inhibit PLK1 in the enzymatic assay at the nM level and exhibit good activity in cell proliferation on A2780 cells. Furthermore, these compounds showed high levels of selectivity on a panel of unrelated kinases, as well as against PLK2 and PLK3 isoforms. Additionally, the compounds show acceptable oral bioavailability in mice making these inhibitors suitable candidates for further in vivo activity studies.
authors.affiliation: Nerviano Medical Sciences srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, (MI), Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Caruso
authors.forename: Barbara
authors.initials: B
authors.lastname: Valsasina
authors.forename: Dario
authors.initials: D
authors.lastname: Ballinari
authors.forename: Jay
authors.initials: J
authors.lastname: Bertrand
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Brasca
authors.forename: Marina
authors.initials: M
authors.lastname: Caldarelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Cappella
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.forename: Laura M
authors.initials: LM
authors.lastname: Gianellini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scolaro
authors.forename: Italo
authors.initials: I
authors.lastname: Beria
mesh_terms: D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004798:Enzymes / Q000737:chemistry; D006801:Humans; D051379:Mice; D008956:Models, Chemical; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; D000097868:Polo-like Kinases
chemical_list: D018797:Cell Cycle Proteins; D004798:Enzymes; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011728:Pyridones; D011743:Pyrimidines; D011758:Pyrroles; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; C518526:1,5,6,7-Tetrahydro-4H-pyrrolo(3,2-c)pyridine-4-one; C573774:5-(2-amino-pyrimidin-4-yl)-1H-pyrrole; C486256:PLK3 protein, human; D000097868:Polo-like Kinases; C496126:PLK2 protein, human