Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 27, Issue 4, Pages 589-603Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2018.12.029
Keywords
3-Aryl-4-indolyl-maleimides; IDH1/R132H inhibitors; Tumor 2-HG; Synthesis
Funding
- Natural Science Foundation of Zhejiang [LY18H300009]
- Postdoctoral Science Foundation of China [2014M550256]
- State Key Laboratory of Drug Research [SIMM1601KF-04]
- National Natural Science Foundation of China [81501310]
- Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12020328]
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A series of 3-aryl-4-indolylmaleimide IDH1/R132H inhibitors with a novel structure was obtained by high-throughput screening and structure-based optimization. Most compounds such as 7a, 7d, 7h, 7i, 7k and 7o showed high inhibitory effects on IDH1/R132H and were highly selective against IDH1/WT, IDH2/WT, GDH, GK, and FBP. Evaluation of the biological activities and function at cellular level showed that compounds 7h, 7i and 7k could effectively suppress the production of 2-hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Additionally, 7h could reversed the differentiation block of the myeloid leukemic cell line, TF-1, caused by the overexpression of IDH1/R132H. We also explore the structure-activity relationship based on the experimental data, with an attempt to pave the way for future studies.
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