Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied β adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98 – 3.30 μM), compared to propranolol (59.5 – 75.8 μM). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 μM for 5m, partially inhibited at 50 μM for propranolol), induce cell apoptosis and cell cycle arrest in the G₂/M phase (both observed at 1 μM). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.

恶性黑色素瘤（MM）是皮肤癌中发病率和死亡率最高的类型。在本文中，受先前报道的普萘洛尔（一种广泛使用的β肾上腺素受体拮抗剂作为心血管药物）的抗黑素瘤作用的启发，我们着手根据药物重用策略开发其作为抗黑素瘤疗法的潜力。与普萘洛尔（59.5 – 75.8μM）相比，普萘洛尔的结构优化产生了5m，对人黑素瘤细胞生长（1.98 – 3.30μM）的效力显着提高。进一步的研究表明5m可以抑制黑素瘤细胞系的集落形成（在2μM下完全消失5m，在普萘洛尔下部分抑制在50μM时），诱导细胞凋亡和G细胞的停滞₂ / M相（均在1μM处观察到）。初步机制研究表明5m可能破坏细胞微管网络，这表明微管蛋白是潜在的靶标。对接研究为5m与微管蛋白之间的相互作用提供了结构上的见识。总而言之，我们的研究提出了将心血管药物重新定向为抗黑素瘤药物的药物再利用案例。