Asperspiropene A, a novel fungal metabolite as an inhibitor of cancer-associated mutant isocitrate dehydrogenase 1

作者：He, Yan; Zheng, Mengzhu; Li, Qin; Hu, Zhengxi; Zhu, Hucheng; Liu, Junjun; Wang, Jianping; Xue, Yongbo^*; Li, Hua^*; Zhang, Yonghui^*

来源：Organic Chemistry Frontiers, 2017, 4(6): 1137-1144.

DOI：10.1039/c6qo00847j

• NATURAL-PRODUCTS
• SELECTIVE-INHIBITION
• DRUG DISCOVERY
• IDH1

In silico screening of an in-house natural product database and confirmatory bioassays led to the identification of asperspiropene A (1) as an inhibitor of cancer-associated mutant IDH1. Compound 1, a meroterpenoid with a highly functionalized 1,8-dioxaspiro[4.5] decane motif, showed potent ability to inhibit mutant IDH1 with inhibition constant (Ki) values as low as 0.27 mu M. The half effective concentration (EC50) of 1 for reducing the cellular concentration of D2HG in HT1080 cells was 8.5 ae M. Molecularly, treatment with 1 led to reduced levels of the H3 K9me3 signal in the HT1080 cells. To the best of our knowledge, 1 is the first fungal metabolite reported to exhibit inhibitory activity against mutant IDH1.

• 出版日期2017-6-1
• 单位华中科技大学; 沈阳药科大学