Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Korea.
Int J Mol Sci. 2017 Dec 28;19(1):77. doi: 10.3390/ijms19010077.
Drug repositioning is the application of the existing drugs to new uses and has the potential to reduce the time and cost required for the typical drug discovery process. In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic and cosmetic purposes. Structure-based virtual screening predicted inhibitor candidates from the US Food and Drug Administration (FDA)-approved drugs. Enzyme assays confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor with the inhibitory constant of 52 μM. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibition; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constant of mercaptopurine (16 μM) was comparable to that of the well-known inhibitor kojic acid (13 μM). The cell-based assay using B16F10 melanoma cells confirmed that the compounds inhibit mammalian tyrosinase. Particularly, 50 μM thioguanine reduced the melanin content by 57%, without apparent cytotoxicity. Cheminformatics showed that the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors.
药物重定位是将现有药物应用于新用途，具有缩短典型药物发现过程所需时间和降低成本的潜力。在这项研究中，我们将用于治疗急性白血病的硫嘌呤药物重新定位为新型酪氨酸酶抑制剂。酪氨酸酶在黑色素生物合成中催化两个连续的氧化反应：将酪氨酸转化为二羟苯丙氨酸（DOPA）和 DOPA 转化为多巴醌。人们正在持续努力发现用于治疗和美容目的的酪氨酸酶小分子抑制剂。基于结构的虚拟筛选从美国食品和药物管理局 (FDA) 批准的药物中预测抑制剂候选物。酶测定证实硫嘌呤白血病药物硫鸟嘌呤是一种酪氨酸酶抑制剂，抑制常数为 52 μM。另外两种硫嘌呤药物巯基嘌呤和硫唑嘌呤也被评估为其对酪氨酸酶的抑制作用；巯基嘌呤的抑制作用强于硫鸟嘌呤，而硫唑嘌呤则抑制作用较差。巯基嘌呤（16 μM）的抑制常数与著名抑制剂曲酸（13 μM）相当。使用 B16F10 黑色素瘤细胞的细胞测定证实了这些化合物对哺乳动物酪氨酸酶的抑制作用。特别是 50 μM 的硫鸟嘌呤使黑色素含量减少了 57%，而没有明显的细胞毒性。化学信息学表明，硫嘌呤药物与已知的酪氨酸酶抑制剂没有多少化学相似性。
