S-phase inhibition of cell cycle progression by a novel class of pyridopyrimidine tyrosine kinase inhibitors.
Increased activity of the src family of oncogenic tyrosine kinases is seen in many human tumors and pharmacologic inhibitors of these kinases are investigated as potential anti-tumor agents. A family of pyrido [2, 3-d] pyrimidine compounds (PD) has been characterized as selective inhibitors of Src kinases. We studied the effects of this class of compounds on cancer cell lines and found that they were highly specific inhibitors of cell cycle progression. These compounds inhibit cells either in the mitotic phase or in mid S-phase; these two activities are mutually exclusive: no compound exerts both activities. We undertook experiments to determine the mechanistic basis for these differences and found additional biochemical activities associated with the S-phase inhibitors. Treatment of cells with the S-phase blocker PD179483 causes abnormal and persistent hyperactivation of Cdk2 and Cdc2 due to Tyr-15 dephosphorylation. These effects were associated with hyperphosphorylation of the upstream regulatory kinase Myt1 and Wee1. They were not observed with the anti-mitotic compounds. Furthermore, the S-phase inhibitors PD179483 and PD166326, but not the anti-mitotic compounds, inhibit Wee1 in vitro at concentrations that cause S-phase block in vivo. These data identify a novel subset of pyridopyrimidine compounds which are inhibitors of src and Wee1 kinases and which inhibit tumor cell growth through cell cycle arrest in mid S-phase.
Mizenina
Olga A
OA
Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Moasser
Mark M
MM
D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000819:agonists / Q000502:physiology; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D011728:Pyridones / Q000378:metabolism; D011743:Pyrimidines / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D016196:S Phase / Q000502:physiology*
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; C473352:PD 166326; D011725:Pyridines; D011728:Pyridones; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2