Novel Flavonoid Derivatives Show Potent Efficacy in Human Lymphoma Models.

Background: Despite significant therapeutic progress, many lymphoma subtypes remain difficult to manage due to resistance, relapse, and dose-limiting toxicity. Methods: To elucidate the mechanism of action of the semi-synthetic flavonoid derivative (SND) compounds, we conducted a screening of cancer cell lines using proliferation, cell cycle, and apoptosis assays. We then performed computational modeling of the compounds' binding to tubulin, and finally evaluated in vivo activity using nanoNail technology alongside xenograft experiment. Results: Here, we describe a series of SNDs that exhibit low-nanomolar to picomolar cytotoxicity across multiple lymphoma models, including those resistant to BTK and PI3K inhibitors. Mechanistic studies show that these compounds trigger robust apoptosis via cytoskeletal disruption and mitochondrial dysfunction. Notably, SND207 also potently inhibits Protein Kinase N1, suggesting a synergistic link between kinase blockade and cytoskeletal interference. High-throughput profiling places them near classical microtubule agents, although tubulin assays indicate more nuanced mechanisms than straightforward stabilization or depolymerization. In murine xenografts, SND207 significantly reduced tumor burden, and its combination with a BTK inhibitor demonstrates potential synergy. Furthermore, localized NanoNail delivery achieves high intratumoral drug concentrations at low doses, underscoring a favorable therapeutic index. Conclusions: Overall, these findings highlight the translational promise of the SND series for future studies in the lymphoma field. Clinical Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.