Publication: DISCOVERY, STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF BENZYLIDENEACETOPHENONES AND METHOXYPHENOLS TARGETING TOLL-LIKE RECEPTOR-4 (TLR-4) AND THEIR MOLECULAR MECHANISMS IN CANCER
Date
2014
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International Medical University
Abstract
Toll-like receptor 4 (TLR-4) is recognised for its role in host innate immunity. Studies on TLR-4 over-activation had linked it to cancer survival and progression. Nevertheless, there is no TLR-4 inhibitor available for cancer treatment. Therefore, the aim of this project is to identify small molecules as TLR-4 inhibitors for cancer treatment. Computational screening methods were used to identify potential TLR-4 ligands (hits). In silico model was found to be in agreement with the results from the in vitro TLR-4 signalling assay. Lead compounds were then designed. Molecular docking reported that a potent TLR-4 inhibitor forms strong binding with both TLR-4 and myeloid differentiation 2 (MD-2). NF-κB reporter assay and Griess assay studies further confirmed these lead compounds induced potent and selective TLR-4 inhibitory effects. Immunoblotting on macrophages and HEK-BlueTM hTLR4 cells further confirmed that the most potent lead compounds, BZD3 and EP13, inhibited lipopolysaccharide (LPSEc) induced MyD88 dependent pathway, but not MyD88 independent pathway in macrophages and HEK-BlueTM hTLR-4 cells. These two lead compounds also induced potent cancer specific anti-proliferative effects and
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apoptotic cell death in cancer cells. TLR-4 and MD-2 ELISA also confirmed that BZD3 and EP13 exhibited TLR-4 inhibitory effects on cancer cells by lowering the expression of TLR-4 and MD-2 levels in the cancer cells. Immunoblotting experiments supported that BZD3 and EP13 inhibited the phosphorylation of downstream MyD88 dependent and MyD88 independent pathways in cancer cells. In conclusion, this study has identified a panel of TLR-4 inhibitors that may play a role in cancer survival and progression.
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Keywords
Toll-Like Receptor 4, Molecular Mechanisms of Pharmacological Action, Neoplasms, Structure-Activity Relationship