I-8, a novel inhibitor of mutant IDH1, inhibits cancer progression in vitro and in vivo

Isocitrate dehydrogenase 1 mutations have been discovered in an array of hematologic malignancies and solid tumors. These mutations could cause the production of high levels of 2-hydroxyglutarate, which in turn implicated in epigenetic changes and impaired cell differentiation. Here, we described th...

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Bibliographic Details
Published in:European journal of pharmaceutical sciences 2019-12, Vol.140, p.105072-105072, Article 105072
Main Authors: Jia, Panli, Wu, Yao, Du, Hongzhi, Yang, Lijun, Zhang, Zhibo, Ma, Tianfang, Li, Sun, Yuan, Shengtao, Lu, Ligong, Zha, Xiaoming
Format: Article
Language:English
Subjects:
2-Hydroxyglutarate
Actins - metabolism
Animals
Antineoplastic Agents - chemistry
Cell Differentiation - drug effects
Cell Line, Tumor
Cell Survival - drug effects
Compound I-8
Differentiation
Dose-Response Relationship, Drug
Enzyme Inhibitors - chemistry
Epigenesis, Genetic
Glutarates - metabolism
Histone methylation
Histones - metabolism
Humans
Isocitrate Dehydrogenase - antagonists & inhibitors
Isocitrate Dehydrogenase - genetics
Isocitrate dehydrogenase 1
Methylation - drug effects
Mice, Inbred BALB C
Mice, Nude
Molecular Docking Simulation
Mutant IDH1 inhibitor
Mutation
Protein Binding
Protein Conformation
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Summary:Isocitrate dehydrogenase 1 mutations have been discovered in an array of hematologic malignancies and solid tumors. These mutations could cause the production of high levels of 2-hydroxyglutarate, which in turn implicated in epigenetic changes and impaired cell differentiation. Here, we described the characterization of compound I-8, a novel mutant IDH1 inhibitor, both in vitro and in vivo. Compound I-8 specifically inhibited 2-HG production, reduced histone methylation levels, induced differentiation and depleted stem characteristics in engineered and endogenous IDH1 mutant cells. In addition, oral administration of I-8 also significantly suppressed 2-HG production and histone methylation with dose of 150 mg/kg. And I-8 treatment also could induce differentiation and attenuate stem characteristics in tumor tissue. Together, these studies indicated that compound I-8 has clinical potential in tumor therapies as a effective mutant IDH1 inhibitor, and provided scientific guidance for the development of mutant IDH1 inhibitor in the future. [Display omitted]
ISSN:0928-0987
1879-0720
DOI:10.1016/j.ejps.2019.105072