Title
Asperspiropene A, a novel fungal metabolite as an inhibitor of cancer-associated mutant isocitrate dehydrogenase 1
Author
Yan He, Mengzhu Zheng, Qin Li, Zhengxi Hu, Hucheng Zhu, Junjun Liu, Jianping Wang, Yongbo Xue, Hua Li, Yonghui Zhang
Year
2017
Journal
Organic Chemistry Frontiers
Abstract
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 μM. The half effective concentration (EC50) of 1 for reducing the cellular concentration of D2HG in HT1080 cells was 8.5 μM. 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.
Instrument
J-810
Keywords
Circular dichroism, Absolute configuration, Natural products, Medicinal