Abstract 7140: A new series of flavonoid derivatives with anti-cancer activity includes SDN207, SND210, SND524, and SND562 as potent microtubule-targeting agents

Abstract Background: Plant-derived compounds, including flavonoids, can be potent anti-cancer agents, but low bioavailability, lack of specificity, and complexity in their synthesis can hamper their clinical development. Here, we present seven novel flavonoid derivatives, and test them for their anti-tumor activity in various models derived from hematological cancers and solid tumors. Methods: MTT assessed anti-proliferative activity after 72h of exposure to increasing concentrations of drugs. Tubulin Polymerization Assay was performed with 3-fold dilutions (15-0.02 μM), compared to paclitaxel (1-3 μM) or vinblastine (3 μM) as references. The OncolinesProfiler analysis was used to compare IC50 fingerprints determined on the Oncolines cell line panel to the IC50 fingerprints of 213 pre-profiled reference drugs. Results: SDN207, SND210, SND216, SND462, SND504, SND524, and SND562 were designed and synthesized using a flavonoid polyphenol scaffold selectively modified to markedly increase cytotoxicity towards cancer cells. All seven compounds showed dose-dependent anti-proliferative activity across 15 lymphoma cell lines derived from germinal center B-cell-like (GCB) diffuse large B cell lymphoma (DLBCL) (n=6), activated B cell-like (ABC) DLBCL (n=2), mantle cell lymphoma (n=4), and marginal zone lymphoma (MZL) (n=3). Activity in the nM range was seen with five compounds: SDN207 (median IC50 1.6 nM; 95%CI, 1.3-3.2), SND210 (1.4 nM; 95%CI, 0.9-3.3), SND216 (19.5 nM; 95%CI, 10-38 nM), SND562 (28.9 nM; 95%CI, 15.4-57.7), and SND524 (46.7 nM; 95%CI, 32-133.3). Both other compounds had a median IC50 of 2 μΜ (SND462, 95%CI, 1.1-4.5 μM; SND504, 95%CI, 0.5-3.9 μM). There were no differences based on lymphoma histology. The anti-tumor activity was maintained in MZL cell lines with acquired resistance to BTK and PI3K inhibitors (n=3). Six compounds were also assessed for their anti-tumor activity in models other than lymphomas (SDN207, n=31; SND210, n=20; SND462, n=4; SND504, n=4; SND524, n=9; SND562, n=35), confirming the higher activity for SDN207, SND210, SND562, and SND524. Regarding the mechanism of action, up to now, a tubulin polymerization assay was performed for three compounds. Microtubule depolymerization (SND207), and microtubule polymerization (SND524, SND562) were observed at concentrations as low as 20 nM. The OncolinesProfiler identified the tubulin-targeting agents vinblastine, vincristine, paclitaxel, and docetaxel among the top reference compounds most correlated with SND207 and SND210 (i.e., Pearson correlation > 0.5). Conclusions: Novel compounds developed using plant-derived skeletons have shown in vitro anti-tumor activity in lymphomas, leukemias, and solid tumors, including models of resistance to targeted agents. Microtubule targeting appeared as a possible mechanism of action for at least four of them. Citation Format: Alberto J. Arribas, Eleonora Cannas, Eugenio Gaudio, Paulina Biniecka, Dan Stoicescu, Francesco Bertoni. A new series of flavonoid derivatives with anti-cancer activity includes SDN207, SND210, SND524, and SND562 as potent microtubule-targeting agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7140.