tae226 and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

The outcomes for relapsed and metastatic Ewing sarcoma (EWS) is extremely poor. Therefore, it is important to identify the tumor-specific targets in these intractable diseases. High focal adhesion kinase (FAK) transcript expression levels in EWS cell lines are known. TAE226 is a dual inhibitor of FAK and insulin-like growth factor-I receptor (IGF-IR), while PF-562,271 is a dual inhibitor of FAK and proline-rich tyrosine kinase 2. We compared the cytotoxicity of TAE226 and PF-562,271 toward three EWS cell lines. TAE226 strongly inhibited proliferation of three cell lines when compared with PF-562,271. Furthermore, we investigated the efficacy of TAE226 as well as its mechanism of action against EWS. A stable EWS cell line with FAK and IGF-IR knocked down was established, and microarray analysis revealed dysregulated expression in various pathways. TAE226 treatment of EWS cell lines induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. We demonstrated that TAE226 drastically inhibits the local growth of primary tumors and metastasis in EWS using mouse models. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.

Topics: Animals; Apoptosis; Biomarkers; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Focal Adhesion Protein-Tyrosine Kinases; Humans; Mice; Morpholines; Neoplasm Staging; Phosphorylation; Protein Kinase Inhibitors; Receptor, IGF Type 1; Sarcoma, Ewing; 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

Neurogenesis in the cerebral infarction after an ischemic event is important to the rehabilitation of patients. However, the mechanism of angiogenesis around cerebral ischemia is not clear. Our study designed to test whether the nerve growth factor (NGF)-P-focal adhesion kinase (FAK) signaling pathway for associations with angiogenesis plays a key role in post-acute cerebral ischemia of rats. Firstly, we implanted the Matrigel, a carrier of basement membrane matrix, into the abdominal skin of rats to identify the relevant components of the NGF-P-FAK signaling pathway related to angiogenesis. Secondly, we used a model established by ligation of the middle cerebral artery (MCA) to observe the effect of the same signal pathway on angiogenesis in the subventricular and subgranular zones of the dentate gyrus(SVG and SGZ). The results showed that the tissue scores was significantly increased by NGF. However, the tissue scores was signifcaintly decreased by FAK inhibitor TAE226. Furthermore, CD31 and α-SMA were significantly increased by NGF and were decreased by anti-NGF and TAE226 in Matrigel. The P-FAK protein expression in Matrigel was markedly increased by NGF and decreased by TAE226. In the SVZ and SVG of cerebral ischemia, the numbers of BrdU-positive cells were significantly increased by NGF and decreased by TAE226, respectively. Our findings suggest that the therapy targeting the NGF-P-FAK signaling pathway may be an option for patients suffering from cerebral ischemia.

Topics: Animals; Brain; Brain Ischemia; Cell Proliferation; Disease Models, Animal; Focal Adhesion Protein-Tyrosine Kinases; Male; Morpholines; Neovascularization, Physiologic; Nerve Growth Factor; Neurogenesis; Neurons; Rats; Rats, Sprague-Dawley; Signal Transduction

TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). In this study, we investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The anti-tumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity. In summary, we showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; ErbB Receptors; Focal Adhesion Protein-Tyrosine Kinases; Gefitinib; Humans; Lung Neoplasms; Mice; Morpholines; Mutation; Protein Binding; Protein Interaction Domains and Motifs; Protein Kinase Inhibitors; Quinazolines; Receptor, IGF Type 1; Xenograft Model Antitumor Assays