Synthesis of Small Molecule Inhibitors of Inflammatory Cytokine Signaling Pathways
Additional Funding Sources
The project described was supported by Institutional Development Awards (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant Nos. P20GM103408 and P20GM109095. We also acknowledge support from The Biomolecular Research Center at Boise State with funding from the National Science Foundation, Grant Nos. 0619793 and 0923535, the MJ Murdock Charitable Trust, the Idaho State Board of Education, Boise State University Department of Chemistry and Biochemistry, and METAvivor.
Presentation Date
7-2018
Abstract
While there have been significant advances in treatments for pre-metastatic breast cancer, the five-year survival rate post-metastasis remains an abysmal 23%. Inflammatory cytokines (IC) are involved in the activation of the STAT3 signaling pathway, which is capable of promoting the invasive potential of cancer cells during the preliminary stages of the metastatic cascade. This has led to an interest in the development of small molecule inhibitors (SMIs) of the IC responsible. Previously, an enzyme-linked immunosorbent assay (ELISA) demonstrated that IC-SMI-10 inhibited the STAT3 signaling pathway. The aim of this research is to synthesize, characterize, and access the inhibitory activity of optimized second-generation IC-SMI-10 analogs with the goal of producing an SMI with a greater propensity to disrupt signaling and prevent breast cancer metastasis. The current approach for optimization involves converting the furan core to either a thiophene or pyrrole, and also modifying the aryl substituents to increase the potential for hydrogen bonding and to enhance solubility. It is envisioned that these alterations will generate an SMI that is more effective, and has more desirable drug-like properties, which will ideally result in a new drug that prevents cancer metastasis.
Synthesis of Small Molecule Inhibitors of Inflammatory Cytokine Signaling Pathways
While there have been significant advances in treatments for pre-metastatic breast cancer, the five-year survival rate post-metastasis remains an abysmal 23%. Inflammatory cytokines (IC) are involved in the activation of the STAT3 signaling pathway, which is capable of promoting the invasive potential of cancer cells during the preliminary stages of the metastatic cascade. This has led to an interest in the development of small molecule inhibitors (SMIs) of the IC responsible. Previously, an enzyme-linked immunosorbent assay (ELISA) demonstrated that IC-SMI-10 inhibited the STAT3 signaling pathway. The aim of this research is to synthesize, characterize, and access the inhibitory activity of optimized second-generation IC-SMI-10 analogs with the goal of producing an SMI with a greater propensity to disrupt signaling and prevent breast cancer metastasis. The current approach for optimization involves converting the furan core to either a thiophene or pyrrole, and also modifying the aryl substituents to increase the potential for hydrogen bonding and to enhance solubility. It is envisioned that these alterations will generate an SMI that is more effective, and has more desirable drug-like properties, which will ideally result in a new drug that prevents cancer metastasis.
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