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Issue 6, 2017
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Asperspiropene A, a novel fungal metabolite as an inhibitor of cancer-associated mutant isocitrate dehydrogenase 1

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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.

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

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Publication details

The article was received on 23 Dec 2016, accepted on 28 Feb 2017 and first published on 01 Mar 2017


Article type: Research Article
DOI: 10.1039/C6QO00847J
Citation: Org. Chem. Front., 2017,4, 1137-1144
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    Asperspiropene A, a novel fungal metabolite as an inhibitor of cancer-associated mutant isocitrate dehydrogenase 1

    Y. He, M. Zheng, Q. Li, Z. Hu, H. Zhu, J. Liu, J. Wang, Y. Xue, H. Li and Y. Zhang, Org. Chem. Front., 2017, 4, 1137
    DOI: 10.1039/C6QO00847J

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