tae226 and Neoplasms

Focal adhesion kinase (FAK) is overexpressed in highly invasive and metastatic cancers. To identify novel FAK inhibitors, we designed and synthesized various thieno[3,2-

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; fms-Like Tyrosine Kinase 3; Focal Adhesion Kinase 1; Humans; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Molecular Structure; Neoplasm Metastasis; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Pyrimidines; Structure-Activity Relationship; Thiophenes; Xenograft Model Antitumor Assays

A dual inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor 1 receptor (IGF-1R), TAE226, was evaluated in a panel of cancer cell lines, MIA PaCa-2 human pancreatic tumor and 4T1 murine breast tumor models. The profiling data were generated during the drug discovery research prior to the first publication of TAE226 appeared in 2007 (Liu et al. in Mol Cancer Ther 6:1357-1367, 2007; Shi et al. in Mol Carcinog 46(6):488-496, 2007; Halder et al. in Cancer Res 67(22):10976-10983, 2007).

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Female; Focal Adhesion Protein-Tyrosine Kinases; Humans; Mice, Inbred BALB C; Mice, Nude; Morpholines; Neoplasms; Protein Kinase Inhibitors; Receptor, IGF Type 1; Signal Transduction

A series of 1,3,5-triazinic inhibitors of focal adhesion kinase (FAK) has recently been shown to exert antiangiogenic activity against HUVEC cells and anticancer efficacy against several cancer cell lines. In this report, we designed and synthesized a series of new compounds containing a 1,2,4-triazine core as novel scaffold for FAK inhibitors. These compounds displayed 10

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Focal Adhesion Protein-Tyrosine Kinases; Humans; Molecular Docking Simulation; Neoplasms; Protein Kinase Inhibitors; Structure-Activity Relationship; Triazines

Neoangiogenesis plays an important role in tumor growth and metastasis. Evaluation of new anti-angiogenic targets may broaden the armament for future therapeutic concepts. Focal adhesion kinase (FAK), expressed in endothelial and tumor cells, is essential for adhesion and mobility of adherent cells. In the current study we analyzed the anti-angiogenic properties of the FAK inhibitor TAE226 on the proliferation of blood outgrowth endothelial cell (OEC) and differentiation of endothelial progenitor cells (EPC), derived from peripheral blood CD133(+) cells, tube formation and on neovascularization in a HT29 xenotransplant model. The effects of TAE226 were compared to those of the rapamycin analogue RAD001. The combination of both drugs was also studied. We showed that HT29 tumor cells and OEC were most sensitive to the action of TAE226 compared to EPC in vitro. In contrast, RAD001 affected the proliferation of both types of endothelial cells stronger than that of HT29 cells. Furthermore we could show that TAE226 inhibited tube formation in a dose dependent manner. In a HT29 subcutaneous tumor model TAE226 and RAD001 diminished MVD at commonly employed doses to a similar degree. Combination of both compounds did not show synergy in vitro or in vivo. Since TAE226 has been shown to inhibit the PI3 kinase, Akt kinase, mTor pathway, addition of RAD001 may not increase this effect. In conclusion, we have shown that treatment with TAE leads to a reduction of neoangiogenesis in vitro and in a mouse model. The effects are mediated by inhibition of angiogenesis and vasculogenic OEC and EPC.

Topics: Animals; Blood Vessels; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Endothelial Cells; Everolimus; Focal Adhesion Protein-Tyrosine Kinases; Humans; Mice; Mice, SCID; Morpholines; Neoplasms; Neovascularization, Pathologic; Organogenesis; Protein Kinase Inhibitors; Sirolimus