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

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Dual Targeting of Norepinephrine Transporter (NET) Function and Thyrointegrin αvβ3 Receptors in the Treatment of Neuroblastoma.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-23 , DOI: 10.1021/acs.jmedchem.0c00537
Ozlem Ozen Karakus ₁ , Kavitha Godugu ₁ , Mehdi Rajabi ₁ , Shaker A Mousa ₁

Affiliation

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.

中文翻译：

去甲肾上腺素转运蛋白（NET）功能和甲状腺整合素αvβ3受体的双重靶向治疗神经母细胞瘤。

通过与聚（乙二醇）（PEG ₄₀₀）的不可裂解键合结合苄基胍（BG）与高亲和力甲状腺素整合素αvβ3拮抗剂三唑四碘甲状腺乙酸（TAT）来治疗去甲肾上腺素转运蛋白（NET）功能）（P）可能为神经母细胞瘤提供了有效的治疗选择。BG-P-TAT是双重靶向剂，靶向NET功能和在神经母细胞瘤和其他神经内分泌肿瘤中过表达的甲状腺整联蛋白αvβ3受体。各种癌细胞和活跃分裂的肿瘤内皮细胞表达甲状腺整联蛋白αvβ3受体。在这项工作中，合成了新型化合物BG-P-TAT并在神经母细胞瘤SK-N-FI细胞系中进行了评估，以改善靶向性并为神经母细胞瘤患者提供新的策略。BG-P-TAT表现出显着抑制神经母细胞瘤肿瘤进展，生长和生存能力的剂量依赖性。总之，BG-P-TAT代表了神经母细胞瘤和其他神经内分泌肿瘤治疗的潜在潜在候选者。

更新日期：2020-07-23

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