Abstract 3647: Combining optimally synthesized quercetin analogs with BRAF inhibitors as a novel synergistic approach to treat melanoma

Abstract The purpose of this research is to generate novel quercetin analogs to use in combination with vemurafenib as a more effective treatment for BRAF-mutated melanoma. Mutations that activate BRAF signaling are found in approximately half of melanoma patients and current clinical use of BRAF inhibitors are not considered curative as recurrence rates are still high. Furthermore, resistance to BRAF inhibitors can occur making the drug no longer effective. Quercetin is a common flavonoid small molecule found in many foods with known antitumorigenic activity. While quercetin has been heavily studied in various cancers, its clinical use is limited by its low bioavailability, most likely due to the presence of numerous phenol groups. We hypothesize that quercetin analogs with higher bioavailability would enhance its antitumorigenic properties, thereby increasing its synergistic potential with BRAF inhibitors. There are two major stages of this research: 1. Making quercetin analogs, generation of BRAF-resistant melanoma cells, and analysis of base-line drug sensitivity and 2. Evaluation of synergistic drug combinations. First, we are using bio isosteric replacement to alter quercetin while maintaining desired biological functions. Numerous studies have focused on altering the phenol groups on quercetin to improve functionality, including methods to convert the phenol to less polar groups that can improve bioavailability and anticancer properties of the analogs. The novelty of these proposed analogs is introducing fluorinated phenol bio isosteres. Initial small-scale synthesis reactions have been run using a diethyl (bromodifluoromethyl)phosphonate reaction with commercially bought quercetin followed by column chromatography, which generated 2-3 products with several phenols functionalized with fluorine. Currently, those fractions are being further purified via additional chromatography, and then specific compounds will be identified using IR-spectroscopy, mass spectrometry, and H1-NMR. Drug sensitivity methods have also been established using CellTitre Glo 2.0 (Promega). Consistent with previously published results, the IC50 for Doxorubicin-HCl on SK-Mel28 cells is ∼1uM. Resistance cells are currently being generated through short-term exposure of SK-Mel28 cells to 20uM vemurafenib. Next, cells will be chronically grown in a low concentration drug. During stage 2, the synthesized quercetin analogs +/- vemurafenib will be tested on both untreated and vemurafenib-resistant melanoma cells. These experiments will examine the potential synergetic effects of these novel combinations while maximizing the clinical relevance to patients with BRAF-mutated melanoma by potentially mitigating the risk of high doses and prolonged use of vemurafenib. Citation Format: Ahlam Armaly, Paige Toran, Victoria Del Gaizo Moore. Combining optimally synthesized quercetin analogs with BRAF inhibitors as a novel synergistic approach to treat melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3647.