Structural highlights
Disease
[IDHC_HUMAN] Defects in IDH1 are involved in the development of glioma (GLM) [MIM:137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors.
Publication Abstract from PubMed
Somatic mutations of isocitrate dehydrogenase 1 (IDH1) at R132 are frequently found in certain cancers such as glioma. With losing the activity of wild-type IDH1, the R132H and R132C mutant proteins can reduce alpha-ketoglutaric acid (alpha-KG) to d-2-hydroxyglutaric acid (D2HG). The resulting high concentration of D2HG inhibits many alpha-KG-dependent dioxygenases, including histone demethylases, to cause broad histone hypermethylation. These aberrant epigenetic changes are responsible for the initiation of these cancers. We report the synthesis, structure-activity relationships, enzyme kinetics, and binding thermodynamics of a novel series of 2-thiohydantoin and related compounds, among which several compounds are potent inhibitors of mutant IDH1 with Ki as low as 420 nM. X-ray crystal structures of IDH1(R132H) in complex with two inhibitors are reported, showing their inhibitor-protein interactions. These compounds can decrease the cellular concentration of D2HG, reduce the levels of histone methylation, and suppress the proliferation of stem-like cancer cells in BT142 glioma with IDH1 R132H mutation.
Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.,Wu F, Jiang H, Zheng B, Kogiso M, Yao Y, Zhou C, Li XN, Song Y J Med Chem. 2015 Sep 10;58(17):6899-908. doi: 10.1021/acs.jmedchem.5b00684. Epub , 2015 Aug 26. PMID:26280302[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wu F, Jiang H, Zheng B, Kogiso M, Yao Y, Zhou C, Li XN, Song Y. Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds. J Med Chem. 2015 Sep 10;58(17):6899-908. doi: 10.1021/acs.jmedchem.5b00684. Epub , 2015 Aug 26. PMID:26280302 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00684
