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Graduate Defense: Roger Vuong

December 8 @ 1:30 pm - 2:30 pm MST

Thesis Information

Title: Synthesis of 2,4-disubstituted Pyrimidines and Quanazolines to Inhabit Oncostatin M

Program: Master of Science in Chemistry

Advisor: Dr. Don Warner, Chemistry and Biochemistry

Committee Members: Dr. Lisa Warner, Chemistry and Biochemistry, and Dr. Cheryl Jorcyk, Biological Sciences

Abstract

Inflammation is an important part of the natural defense mechanism against injury and infection. This process involves the release of mediators such as cytokines, however, a dysregulated inflammatory response can lead to further tissue damage. The oncostatin M (OSM) cytokine was shown to upregulate inflammatory signaling pathways and contribute to diseases such as rheumatoid arthritis, cystic fibrosis, and various cancers. Therefore, OSM is an attractive therapeutic target, however, there are no reported small molecules to attenuate its signaling. This research aims to design and synthesize small molecule inhibitors (SMIs) to disrupt OSM-induced cell signaling. A three-dimensional quantitative structure-activity relationship (3D-QSAR) contour map was developed to ascertain structural features important for the SMIs binding to OSM, and next-generation SMI-27 compounds were designed and computationally docked at site III of OSM to predict their binding energies. After synthesis, the binding affinity, as measured by dissociation constants (KD), of each SMI to OSM was measured using fluorescence quenching assays. It was found that SMI-27F1 had moderate binding with a KD of 25 ± 3 μM and several other SMIs had dissociation constants in the mid-micromolar range. Enzyme-linked immunosorbent assays (ELISAs) were used to determine the inhibition of OSM signaling by measuring relative levels of OSM-induced expression of pSTAT3. Several of the SMIs including SMI-27E6, inhibited OSM signaling and showed reduced levels of pSTAT3. The inhibitory activity of SMI-27E6 demonstrates that a 3D-QSAR model offers a valid approach to designing SMIs since this analog has a carboxyl group that extends further into the site III hydrophobic pocket. This structural change resulted in greater inhibition of OSM signaling, in contrast to SMI-27E5 which lacked this moiety and displayed poorer inhibition. This research adds to the catalog of methods for the rational design of SMIs that could lead to developing a drug for the treatment of OSM-related diseases.