Design, synthesis, and biological evaluation of novel bifunctional thyrointegrin antagonists for neuroblastoma

Receptor-mediated cancer therapy has received much attention in the last few decades. Neuroblastoma and other cancers of the sympathetic nervous system highly express norepinephrine transporter (NET) and cell plasma membrane integrin αvβ3. Dual targeting of the NET and integrin αvβ3 receptors using a Drug-Drug Conjugate (DDC) might provide effective treatment strategy in the fight against neuroblastoma and other neuroendocrine tumors. In this work, we synthesized three dual-targeting BG-P₄₀₀-TAT derivatives, dI-BG-P₄₀₀-TAT, dM-BG-P₄₀₀-TAT, and BG-P₄₀₀-PAT containing di-iodobenzene, di-methoxybenzene, and piperazine groups, respectively. These derivatives utilize to norepinephrine transporter (NET) and the integrin αvβ3 receptor to simultaneously modulate both targets based on evaluation in a neuroblastoma animal model using the neuroblastoma SK-N-F1 cell line. Among the three synthesized agents, the piperazine substituted BG-P₄₀₀-PAT exhibited potent integrin αvβ3 antagonism and reduced neuroblastoma tumor growth and cancer cell viability by >90%. In conclusion, BG-P₄₀₀-PAT and derivatives represent a potential therapeutic approach in the management of neuroblastoma.