Publication Date

12-2018

Date of Final Oral Examination (Defense)

10-19-2018

Type of Culminating Activity

Thesis

Degree Title

Master of Science in Chemistry

Department

Chemistry

Supervisory Committee Chair

Don Warner, Ph.D.

Supervisory Committee Member

Cheryl Jorcyk, Ph.D.

Supervisory Committee Member

Matthew D. King, Ph.D.

Supervisory Committee Member

Lisa Warner, Ph.D.

Abstract

At 30% of all new diagnoses, the most prevalent malignancy for women is breast cancer, which in the United States will result in an estimated 266,000 new cases this year alone. Of the patients diagnosed with breast cancer, approximately 10-15% will develop distant metastases within three years of the initial detection of a primary tumor. For comparison, the five-year survival rate for localized breast cancer is 99%, whereas, the survival rate for metastatic breast cancer drops drastically to only 27%. The significant difference in survival rates is indicative of a need for a novel treatment strategy for metastatic breast cancer.

Oncostatin M (OSM), a member of the interleukin-6 family of cytokines, has been shown in the context of breast cancer to promote epithelial to mesenchymal transition (EMT), promote tumor cell detachment and invasiveness, increase circulating tumor cell (CTC) numbers, induce the expression of proangiogenic factors, and promote lung and bone metastases. For these reasons, the work presented describes the structure-based drug design, synthesis, and preliminary testing of small molecule inhibitors (SMIs) of OSM to be used as a therapeutic treatment method for metastatic breast carcinomas. Based on synthetic accessibility and computational screening, SMIs were synthesized and subsequently evaluated for inhibition of OSM-induced signaling using an enzyme-linked immunosorbent assay (ELISA). The SMIs were further assessed for binding affinity toward OSM using isothermal titration calorimetry (ITC). The results suggested that SMIs capable of inhibiting OSM-induced signaling also exhibited binding to OSM. Furthermore, SMIs not able to bind to OSM correlated with poor inhibition of OSM-induced signaling. Therefore, the preliminary results suggest: specific SMI-OSM binding occurs, SMIs are capable of inhibiting OSM-induced signaling, and that additionally optimized SMIs have the potential to be used as novel therapeutic treatment options for metastatic breast cancer.

DOI

10.18122/td/1501/boisestate

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