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Thesis Defense

Kelsey Skluzacek – October 19 – 1:30 pm – EDUC 112

Title: “Structure-Based Drug Design of Novel Therapeutics Targeting Oncostatin M”

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.

Advisor: Dr. Don Warner, Boise State Department of Chemistry & Biochemistry
Committee: Dr. Cheryl Jorcyk, Boise State Department of Biological Sciences; Dr. Matthew King, Boise State Department of Chemistry & Biochemistry; Dr. Lisa Warner, Boise State Department of Chemistry & Biochemistry


Thesis Defense

Savannah Irving – October 23 – 9:00 am – MPCB 108

Title: “Optimizing the Synthesis of Self-Immolative Poly(hexyl isocyanate)”

Abstract

An optimized synthesis is presented for the anionic polymerization of hexyl isocyanate that undergoes selective depolymerization. This self-immolative polymer contains a reactive detection unit at the terminus of the polymer, that is cleaved from the backbone when a specific stimulus is applied, and results in continuous depolymerization into small molecules. A key aspect of this research was using commercially available reagents to polymerize hexyl isocyanate that resulted in good yields, predictable lengths, and low PDI values. The control over the molecular weight of the polymer was achieved at various lengths, ranging from 200 repeating units to 1,000 repeating units long. Under these optimized conditions, selective depolymerization was accomplished with base responsive, and UV-light responsive poly(hexyl isocyanate)s.

Advisor: Dr. Scott Phillips, Boise State Materials Science & Engineering
Committee: Dr. Adam Colson, Boise State Department of Chemistry & Biochemistry; Dr. Jeunghoon Lee, Boise State Department of Chemistry & Biochemistry