13: Optimization of furan-based small molecules to inhibit breast cancer metastasis

Abstract: Metastatic breast cancer continues to present significant therapeutic challenges, as evidenced by a five-year survival rate hovering around 30–35%. Consequently, there is a pressing requirement for novel therapeutic approaches capable of disrupting the initial stages of metastasis. This study focuses on the development of small-molecule inhibitors (SMIs) designed to target an inflammatory cytokine (IC) implicated in driving epithelial–mesenchymal transition (EMT), angiogenesis, and cell detachment throughout the course of cancer progression. Following a computational high-throughput screening of 1.6 million molecules, 26 potential small-molecule inhibitors (SMIs) were identified. From this selection, SMI-10, a furan-based scaffold, was chosen as the lead compound for further study. The SMI-10L4 analog was synthesized through prior optimization, which involved the removal of a nitro group and the replacement of a diazenyl linker with an amide. Based on fluorescence quenching assays of binding, SMI-10L4 exhibits the most favorable characteristics to date, demonstrating a dissociation constant (KD) of 4.0 ± 1.0 µM. The compound's high aromaticity and planarity have contributed to its low solubility despite this increased potency. We investigated structural changes targeted at lowering aromatic character and enhancing drug-like qualities to overcome this restriction. In earlier studies, deletion of substituents at the 4- and 5-positions of the core scaffold produced varying effects on activity. Building on this, we designed and synthesised new analog libraries targeting each position independently to better understand the structure–activity relationship. To increase chemical diversity, triazole-containing analogs were created at each position using copper-catalysed azide–alkyne cycloaddition (CuAAC). This click chemistry method offers a reliable and effective way to create diverse analogs under mild conditions. This poster will detail how these libraries were created, including protein-binding data and results from cell-based tests, to assess their potential as anti-metastatic agents.