Chen Wenli, Chen Xinying, Zhou Shujia, Zhang Hong, Wang Ling, Xu Jun, Hu Xiaopeng, Yin Wei, Yan Guangmei, Zhang Jingxia
School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University City, Guangzhou 510006, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510080, China.
School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University City, Guangzhou 510006, China.
Steroids. 2016 Jun;110:1-8. doi: 10.1016/j.steroids.2016.03.004. Epub 2016 Mar 8.
AKR1B10 is a member of the human aldo-keto reductase superfamily which is highly expressed in several types of cancers, and has been regarded as a promising cancer therapeutic target. In this paper, a series of polyhydroxy steroids were designed and synthesized to selectively inhibit AKR1B10 activity. The most selective compound, novel compound 6, has an IC50 of 0.83±0.07μM and a selectivity of more than 120-fold for AKR1B10/AKR1B1. Structure-activity relation analyses indicate that hydroxyl at C-19 can significantly improve the selective inhibition of AKR1B10. The binding mode of AKR1B10 and its inhibitors were studied.
AKR1B10是人类醛糖还原酶超家族的成员，在多种癌症中高表达，被视为一个有前景的癌症治疗靶点。本文设计并合成了一系列多羟基甾体以选择性抑制AKR1B10的活性。最具选择性的化合物，新型化合物6，其IC50为0.83±0.07μM，对AKR1B10/AKR1B1的选择性超过120倍。构效关系分析表明，C-19位的羟基可显著提高对AKR1B10的选择性抑制。研究了AKR1B10与其抑制剂的结合模式。
