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

Michele Caruso; Barbara Valsasina; Dario Ballinari; Jay Bertrand; Maria Gabriella Brasca; Marina Caldarelli; Paolo Cappella; Francesco Fiorentini; Laura M Gianellini; Alessandra Scolaro; Italo Beria

doi:10.1016/j.bmcl.2011.11.065

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

Bioorg Med Chem Lett. 2012 Jan 1;22(1):96-101. doi: 10.1016/j.bmcl.2011.11.065. Epub 2011 Nov 23.

Authors

Michele Caruso¹, Barbara Valsasina, Dario Ballinari, Jay Bertrand, Maria Gabriella Brasca, Marina Caldarelli, Paolo Cappella, Francesco Fiorentini, Laura M Gianellini, Alessandra Scolaro, Italo Beria

Affiliation

¹ Nerviano Medical Sciences srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, (MI), Italy.

PMID: 22154349
DOI: 10.1016/j.bmcl.2011.11.065

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.

MeSH terms

Administration, Oral
Algorithms
Animals
Cell Cycle Proteins / antagonists & inhibitors*
Cell Line, Tumor
Cell Proliferation / drug effects
Chemistry, Pharmaceutical / methods
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor / methods
Enzymes / chemistry
Humans
Mice
Models, Chemical
Polo-Like Kinase 1
Protein Isoforms
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins / antagonists & inhibitors*
Pyridones / chemistry*
Pyridones / pharmacology
Pyrimidines / chemical synthesis
Pyrimidines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry*
Pyrroles / pharmacology
Tumor Suppressor Proteins

Substances

1,5,6,7-Tetrahydro-4H-pyrrolo(3,2-c)pyridine-4-one
5-(2-amino-pyrimidin-4-yl)-1H-pyrrole
Cell Cycle Proteins
Enzymes
Protein Isoforms
Proto-Oncogene Proteins
Pyridones
Pyrimidines
Pyrroles
Tumor Suppressor Proteins
PLK3 protein, human
PLK2 protein, human
Protein Serine-Threonine Kinases