Melanoma is a lethal form of skin cancer. Despite recent breakthroughs of BRAF-V600E and PD-1 inhibitors showing remarkable clinical responses, melanoma can eventually survive these targeted therapies and become resistant. To solve the drug resistance issue, we designed and synthesized ligand-drug conjugates that couple cytotoxic drugs, which have a low cancer resistance issue, with the melanocortin 1 receptor (MC1R) agonist melanotan-II (MT-II), which provides specificity to MC1R-overexpressing melanoma. The drug-MT-II conjugates maintain strong binding interactions to MC1R and induce selective drug delivery to A375 melanoma cells through its MT-II moiety in vitro. Furthermore, using camptothecin as the cytotoxic drug, camptothecin-MT-II (compound 1) can effectively inhibit A375 melanoma cell growth with an IC50 of 16 nM. By providing selectivity to melanoma cells through its MT-II moiety, this approach of drug-MT-II conjugates enables us to have many more options for cytotoxic drug selection, which can be the key to solving the cancer resistant problem for melanoma.

中文翻译：

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通过过度表达的黑皮质素 1 受体开发靶向黑色素瘤的配体-药物偶联物

黑色素瘤是一种致命的皮肤癌。尽管最近 BRAF-V600E 和 PD-1 抑制剂的突破显示出显着的临床反应，但黑色素瘤最终可以在这些靶向治疗中存活下来并产生耐药性。为解决耐药性问题，我们设计并合成了配体-药物偶联物，将具有低抗癌性问题的细胞毒性药物与黑皮质素 1 受体 (MC1R) 激动剂 melanotan-II (MT-II) 偶联，后者提供特异性MC1R 过度表达的黑色素瘤。药物-MT-II 偶联物保持与 MC1R 的强结合相互作用，并在体外通过其 MT-II 部分诱导选择性药物递送至 A375 黑色素瘤细胞. 此外，使用喜树碱作为细胞毒药物，喜树碱-MT-II（化合物 1）可以有效抑制 A375 黑色素瘤细胞的生长，IC50 为 16 nM。通过其 MT-II 部分为黑色素瘤细胞提供选择性，这种药物-MT-II 偶联物的方法使我们能够有更多的细胞毒性药物选择选择，这可能是解决黑色素瘤抗癌问题的关键。