Improving the Potency and Drug-Likeness of a Quinoline-Based Small Molecule Inhibitor for Breast Cancer Metastasis

Prior studies have linked the overexpression of an inflammatory cytokine (IC) to metastatic breast cancer. We hypothesize that the cytokine’s signaling pathways can be disrupted by introducing a small molecule inhibitor (SMI) designed to bind competitively at the receptor binding site. Initially, 3 lead SMIs with promising inhibitory activity were discovered, including SMI-26, a quinoline-based inhibitor. Prior optimization followed a quantitative structure-activity relationship (QSAR) approach emphasizing phenyl group optimization through steric and electronic effects. One particularly potent analog, A22, was discovered through a combination of fluorescence and in vitro assays. A more water-soluble variant, S7, was synthesized using a bioisosteric replacement for in vivo mouse model assays. This research expands upon these findings by synthesizing promising analogs with varying carboxylic acid bioisosteres. The goals are to enhance solubility while retaining the potency of their predecessor, A22. SMI-26 analog design, synthesis, and inhibitory properties will be presented to identify an ideal analog for inhibition of metastatic breast cancer.