A Structure-Activity Relationship Study with Isoquinolinone Compounds and Stromal Antigen 2 Mutant Ewing’s Sarcoma Cells and Synthesis of Small Molecules for Anticancer Activity Through TEAD Palmitoylation Inhibition



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There are two distinct projects that will be discussed in this dissertation. The first section will be focused on the structure-activity relationship study with isoquinolinone compounds, and the second on the synthetic approach to small molecules that inhibit the growth of cancer cells through the Hippo signaling pathway. Ewing’s sarcoma is the second most commonly diagnosed pediatric bone cancer. While there are common forms of general treatment available, there are little to no treatments for recurrent cases, as well as malignant tumors. Our collaborators at the Baylor College of Medicine found in a high throughput screening an isoquinolinone compound, StagX1, which is selectively active in inhibiting and decreasing the cell viability of STAG 2 mutant cancer cells in an environment of wild type cancer cells. SAR studies have been performed to find new derivatives with increased the efficacy, general solubility, and plasma stability. Different delivery systems, such as liposomes, have been implemented to help identify the true active compound towards the cancer cell lines. The Hippo signaling pathway is a cell signaling pathway that was recently linked to cancer development and immunotherapy. Mutation or malfunction in the signaling pathway leads to irregular cell growth, especially in the case of tumor cells. To support cell regulation and prevent cancer cell proliferation, the TEAD protein is prohibited from undergoing palmitoylation, in which cell proliferation and anti-apoptosis is prevented. Two small hydrophobic structures were discovered through virtual ligand screening by our collaborators. Two initial synthetic routes were completed to initiate efficient production of products and further advancement in biological and SAR studies.



Structure-activity relationship study