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Graduate Defense: Riley Olsen

July 20 @ 8:00 am - 9:00 am MDT

Thesis Information

Title: Rational Design of 2,4-Disubstituted Quinazoline Small Molecules to Inhibit an Inflammatory Cytokine

Program: Master of Science in Chemistry

Advisor: Dr. Don Warner, Chemistry and Biochemistry

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

Abstract

The inflammatory cytokine Oncostatin M (OSM) plays an important role in breast cancer metastasis, as well as other inflammatory diseases such as inflammatory bowel disease, Crohn’s disease, and several fibrotic diseases. OSM mediates its malignant activity by inducing cell signaling upon binding to its main receptor. We propose to inhibit this OSM-receptor interaction by developing rationally designed small molecule inhibitors (SMIs). In order to identify a lead SMI, computational docking experiments of over 33,000 compounds were docked into the known crystal structure of OSM. These experiments allowed for the development of a pharmacophore probability map that aimed to predict important OSM/SMI interactions. Guided by the generated maps, SMI 27 was generated as a lead compound for inhibiting OSM. Structurally, SMI 27 features a quinazoline core appended to an aryl group at position 2 and an amide group at position 4. A focused library of SMI 27 analogs were synthesized with varying chain lengths and aromatic substituents in the 2 position, as well as various hydrophobic aryl groups in the 4 position. The synthesized molecules were then tested for biological activity using western blot and enzyme linked immunosorbent assays (ELISA), and binding affinity was determined using fluorescence quenching assay. Fluorimetry assays suggest that all SMI-27 analogs directly bind to OSM with low micromolar affinity. Analysis by ELISA has shown that all SMI 27 analogs inhibit STAT3 phosphorylation, and western blot experiments suggest certain analogs deactivate OSM signaling specifically. These and other results are presented herein.