Small molecule inhibitors useful in the treatment of cancer and inflammatory diseases.
- TAK-1 activity can lead to metastasis and cancerous angiogenesis.
- Suppression of TAK-1 has been demonstrated by a set of synthetic analogues based on the natural product 5(Z)-7-oxozeaenol.
TAK1 is a member of the MAPKKK family, is a key mediator of proinflammatory and stress signals. Activation of TAK-1 by proinflammatory cytokines and T and B cell receptors induces the nuclear localization of nuclear factor ÎºB (NF-Kappa B) and the activation of c-Jun N-terminal kinase (JNK)/AP1 and P38, which play important roles in mediating inflammation, immune responses, T and B cell activation, apoptosis and epithelial cell survival. Recently it was shown that the natural product 5(Z)-7-oxozeaenol can effectively inhibit TAK-1 activity, thereby lessening the extent of these cancerous growths. The inventors have created a library of synthetic analogues that surpass the activity of 5(Z)-7-oxozeaenol. In vitro studies reveal that a number of these synthetic analogues are not only sufficiently cytotoxic to tumor cells, but also relatively harmless to normal cell lines. These compounds have also been shown to reduce tumor growth in xenograft mouse models. Additional medicinal chemistry work is being conducted in order to optimize these novel compounds for therapeutic use.
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