Novel Small Molecules Disabling the IL-6/IL-6R/GP130 Heterohexamer Complex
Abstract
Interleukin-6 (IL-6) is a key signaling molecule in breast cancer cells. It is responsible for many cellular responses in both cancer and normal cells, including immune response, cell survival, cell death, and proliferation. Unfortunately, IL-6 may also play a key role in the progression of breast cancer from stage I to stage IV cancer (typically associated with a poor prognosis among breast cancer patients). This change to a more serious cancer is associated with significantly increased levels of IL-6, which is believed to affect the subsequent proliferation and metastasis of the tumor cells by initiating a complex series of molecular signal pathways, specifically the IL-6/JAK2/STAT3 pathway. Therefore, we are examining a new strategy to combat breast cancers by disrupting the initiation of the IL-6 signaling using small synthetic molecules using the natural product madindoline A as a starting point for our studies. Madindoline A (MDL-A) is known to interact with the IL-6 receptor on the surface of the cell and prevent this signaling event. Modification of the chemical structure of MDL-A and new design using it as a structural template should provide more potent and selective derivatives which may be useful therapeutic agents for the treatment of breast cancer. Thus, a multidisciplinary team has been assembled with expertise in computational chemistry, synthetic chemistry and cancer biology in order to design and synthesize the new compounds, and in biochemical and cellular assays to assess the effectiveness of these agents. To date, more than twenty novel analogues have been synthesized and partially tested for their ability to bind to gp130 and inhibit STAT3 phosphorylation. The data obtained during the course of our studies into the anticancer properties of these molecules will be utilized to refine and improve upon our model and our synthetic analogues with the ultimate goal of developing a useful treatment for late stage breast cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2012
- Accession Number
- ADA584824
Entities
People
- Chenglong Li
- James Fuchs
- Jiayuh Lin
Organizations
- Ohio State University