5l57
From Proteopedia
Crystal structure of Iso-citrate Dehydrogenase R132H in complex with a novel inhibitor (compound 13a)
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 PubMedA collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro. Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells.,Jones S, Ahmet J, Ayton K, Ball M, Cockerill M, Fairweather E, Hamilton N, Harper P, Hitchin J, Jordan A, Levy C, Lopez R, McKenzie E, Packer M, Plant D, Simpson I, Simpson P, Sinclair I, Somervaille TC, Small H, Spencer GJ, Thomson G, Tonge M, Waddell I, Walsh J, Waszkowycz B, Wigglesworth M, Wiseman DH, Ogilvie D J Med Chem. 2016 Dec 22;59(24):11120-11137. Epub 2016 Dec 5. PMID:28002956[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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