Isia Bursuker

1H-Pyrazolo[3,4-b]pyridine Inhibitors of Cyclin-Dependent Kinases

1H-Pyrazolo[3,4-b]pyridine 3 (SQ-67563) has been shown to be a potent, selective inhibitor of CDK1/CDK2 in vitro. In cells 3 acts as a cytotoxic agent with the ability to block cell cycle progression and/or induce apoptosis. The solid state structure of 3 bound to CDK2 shows 3 resides coincident with the ATP purine binding site and forms important H-bonding interactions with Leu83 on the protein backbone.

In vitro expression of secondary antitumor immunity by in vivo tumor-sensitized T cells: Inhibition by tumor-induced suppressor T cells

SummaryIn vitro cultivation of memory immune cells from P815- or P388-immune mice with corresponding irradiated tumor cells induced generation of cytolytic T cells (CTL). The induction of CTL generation, as well as the cytolytic activity itself, was tumor-specific. The in vitro generation of CTL from P815- or P388-immune cells was suppressed by spleen cells from mice bearing corresponding progressive tumors (tumor size 15 mm). The tumor-induced suppressor cells suppressed the in vitro generation of CTL, but did not affect their cytolytic function. The suppression was tumor-specific and was mediated by Ly1+2−L3T4+ T cells. Treatment of suppressor cell donors with cyclophosphamide or sublethal γ-radiation completely abolished the ability of their spleen cells to inhibit the in vitro CTL generation.

Interaction of NT-4 and BDNF with gp145trkb receptor: effect on cellular metabolism.

In the present study a silicon microphysiometer (Cytosensor) was applied in investigating interactions of gp145(trkb), a member of the tyrosine kinase receptor family, with different neurotrophic factors. NIH-3T3 cells transfected with gp145(trkb) receptors (NIH3T3/trkB cells) were utilized in the studies. Treatment with brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4) and neurotrophin-3 (NT-3) induced changes in the metabolic rate of NIH3T3/trkB cells. In contrast, no response was observed with nerve growth factor (NGF). The effects of NT-4 and BDNF on NIH3T3/trkB cells were receptor-specific in that they did not induce metabolic rate changes in wild type NIH3T3 cells or cells transfected with either gp140(trkb) (TrkA) or gp145(trkb) (TrkC) receptors. In contrast, NT-3 induced metabolic rate changes in cells transfected with each of the three different Trk receptors. The activity of NT-4 was significantly higher than that of BDNF. K252a, a protein kinase inhibitor, reduced the NT-4- and BDNF-induced response of the NIH3T3/trkB cells. This suggests that the NT-4 and BDNF-induced metabolic rate changes are associated with autophosphorylation of the tyrosine protein kinase residues. This hypothesis is further supported by results of western blot analysis. The results show that interactions of Trk receptors with neurotrophic factors result in metabolic changes in cells expressing the receptors.