I. Targeted protein degradation of TIP60 to regulate Treg cell activity in lung cancer; ; Regulatory T (Treg) cells are significant contributors to immune system suppression. Foxp3 is the key transcriptional regulator of Treg cells, responsible for their development and function. Foxp3 is a target of acetylation by lysine acetyltransferases (KATs), such as TIP60 and P300. The acetylation of Foxp3 regulates Treg cells activity, leading to a suppression of immune responses. TIP60 is the major protein that has been shown to regulate the Treg cell level by interacting with Foxp3. Therefore, targeting TIP60 in a selective manner is significant for the regulation of immune system activity. We designed a library of TIP60 degraders to recruit the Cereblon (CRBN) E3 ubiquitin ligase and promote ligand-induced dimerization of TIP60 and CRBN in cells to degrade TIP60 by the proteasome. By varying linker composition and length, we were able to assess conditions that allow for effective degradation of TIP60 in vitro and in vivo.; ; II. Synthesis of small molecule inhibitors for Gαi-GIV protein-protein interaction to target cell migration in breast cancer.; ; G-protein coupled receptors (GPCRs) are the largest, most diverse group of membrane receptors in eukaryotes, with a crucial role in cell function and activity. Heterotrimeric G proteins are highly utilized signaling nodes and achieving and controlling their activation have been of interest for decades. GIV, a metastasis-related protein expressed in highly invasive cancer cells, binds, and activates Gα, resulting in the dissociation of Gβγ which leads to cell migration in cancer. Therefore, we designed small molecule modulators to target the Gαi-GIV interaction. NMR binding studies, along with computational modeling enabled us to synthesize a library of fluorene-sulfonamide analogues. In vivo studies after treating the MDA-MB-231 bearing mice with the most potent analogue from the library showed a decrease in tumor cell migration. 2023-03-30T00:00:00Z