Zhou Yang, Mowlazadeh Haghighi Saghar, Liu Zekun, Wang Lingzhi, Hruby Victor J, Cai Minying
Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States.
ACS Pharmacol Transl Sci. 2020 Aug 18;3(5):921-930. doi: 10.1021/acsptsci.0c00072. eCollection 2020 Oct 9.
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 . 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.
黑色素瘤是一种致命的皮肤癌。尽管最近BRAF-V600E和PD-1抑制剂取得了突破，显示出显著的临床反应，但黑色素瘤最终可能会在这些靶向治疗中存活并产生耐药性。为了解决耐药问题，我们设计并合成了配体-药物缀合物，将耐药性较低的细胞毒性药物与黑皮质素1受体（MC1R）激动剂黑素细胞刺激素-II（MT-II）偶联，MT-II可特异性作用于MC1R过表达的黑色素瘤。药物-MT-II缀合物与MC1R保持强烈的结合相互作用，并通过其MT-II部分将药物选择性递送至A375黑色素瘤细胞。此外，以喜树碱作为细胞毒性药物，喜树碱-MT-II（化合物1）能够有效抑制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，药物-MT-II缀合物的这种方法使我们在细胞毒性药物选择上有更多选择，这可能是解决黑色素瘤耐药问题的关键。
