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

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 (K_i) 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.