Dual Targeting of Norepinephrine Transporter (NET) Function and Thyrointegrin αvβ3 Receptors in the Treatment of Neuroblastoma.

Ozlem Ozen Karakus, Kavitha Godugu, Mehdi Rajabi, Shaker A Mousa

Journal of medicinal chemistry 2020 Jul 23

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Therapeutic targeting of the norepinephrine transporter (NET) function with benzylguanidine (BG), conjugated with the high-affinity thyrointegrin αvβ3 antagonist triazole tetraiodothyroacetic acid, TAT, via noncleavable bonding to poly(ethylene glycol) (PEG400) (P) might allow for effective treatment options in neuroblastoma. BG-P-TAT is a dual-targeting agent, targeting the NET function and the thyrointegrin αvβ3 receptors that are overexpressed in neuroblastoma and other neuroendocrine tumors. Various cancer cells and actively dividing tumor-endothelial cells express the thyrointegrin αvβ3 receptors. In this work, the novel compound BG-P-TAT was synthesized and evaluated in the neuroblastoma SK-N-FI cell line for improved targeting and to offer a new strategy for patients with neuroblastoma. BG-P-TAT demonstrated significant suppression of neuroblastoma tumor progression, growth, and viability in a dose-dependent manner. In conclusion, BG-P-TAT represents a potential lead candidate for the treatment of neuroblastoma and other neuroendocrine tumors.

Citation

Ozlem Ozen Karakus, Kavitha Godugu, Mehdi Rajabi, Shaker A Mousa. Dual Targeting of Norepinephrine Transporter (NET) Function and Thyrointegrin αvβ3 Receptors in the Treatment of Neuroblastoma. Journal of medicinal chemistry. 2020 Jul 23;63(14):7653-7662