Kabir Aurangazeb, Endo Satoshi, Toyooka Naoki, Fukuoka Mayuko, Kuwata Kazuo, Kamatari Yuji O
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Labolatory of Biochemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi Gifu 501-1196, Japan.
J Biochem. 2017 Feb 1;161(2):215-222. doi: 10.1093/jb/mvw063.
Inhibitors of AKR1B10 belonging to the aldo-keto reductase (AKR) superfamily are considered promising candidates for anti-cancer drugs. AKR1B1, a structurally similar isoform of AKR1B10, is involved in glucose metabolism. Thus, selective inhibition of AKR1B10 is required for the development of anti-cancer drugs. In this study, we first compared correlations between melting temperature and the 50% inhibition concentration obtained from differential scanning fluorimetry (DSF) and an enzyme inhibitory experiment, respectively, and a good correlation was found, except for compounds with low solubility. This result indicates that the DSF method is useful for drug screening for the AKR superfamily. We then evaluated their selectivity as inhibitors against all seven major human AKR1 family proteins and found that C18 is most specific for AKR1B10.
属于醛酮还原酶（AKR）超家族的AKR1B10抑制剂被认为是很有前景的抗癌药物候选物。AKR1B1是AKR1B10结构相似的同工型，参与葡萄糖代谢。因此，抗癌药物的研发需要选择性抑制AKR1B10。在本研究中，我们首先分别比较了差示扫描荧光法（DSF）和酶抑制实验得到的熔解温度与50%抑制浓度之间的相关性，发现除了低溶解度的化合物外，二者具有良好的相关性。这一结果表明DSF方法可用于AKR超家族的药物筛选。然后，我们评估了它们作为针对所有七种主要人类AKR1家族蛋白的抑制剂的选择性，发现C18对AKR1B10最具特异性。
