Development of New Chemotherapeutics for Head & Neck Squamous Cell Carcinoma (HNSCC)

The signal transducers and activators of transcription STAT3 and STAT1 share common structure and targets, but they play opposing roles in tumorigenesis. While STAT3 is considered an oncogene that promotes cell survival, proliferation, motility, and immune tolerance, STAT1 enhances inflammation, favors cell cycle arrest, and apoptosis in most tumor cells. STAT3 has been found to be constitutively active in head and neck squamous cell carcinomas (HNSCC) where it promotes the cell cycle and prevents apoptosis, resulting in the proliferation and survival of HNSCC cells. We hypothesize that a small molecule inhibitor of STAT3 that is selective over STAT1 in HNSCC would serve as a powerful cancer therapeutic. The lead compound 669 that was identified through high content screening (HCS) displayed a pSTAT3 inhibition with 10-fold greater selectivity over pSTAT1 in HNSCC cells (pSTAT3 IC50 5.50 ± 1.50 μM (n = 7) vs. pSTAT1 > 50 μM). The mechanism of 669’s effect on the STAT3 pathway remains unknown, however, it does not proceed by a kinase inhibition pathway. This thesis describes the development of a structure activity relationship (SAR) for pSTAT3 inhibitors related to 669. The key reaction to synthesize these analogs is performed in a microwave reactor, which saves time, and is convenient for parallel synthesis