Research Project
8223252
DESCRIPTION (provided by applicant): The goal of this project is to identify and optimize inhibitors that are specific for the isocitrate dehydrogenase 1 (IDH1). Unbiased genomic sequencing for 22 glioma genomes found recurrent mutation of IDH1 on chromosome 2q33-a gene encoding the cytosolic isoform of IIDH1 associated with the tricarboxylic acid cycle (TCA) that catalyzes the oxidative decarboxylation of isocitrate yielding 1-ketoglutarate and CO2 via NADP+ to NADPH conversion. Subsequent studies confirmed the recurrent IDH mutations in up to 70% of secondary gliomas and in 10% of AML cases. We have found that the somatic mutation of cancer-associated IDH1 is a point mutation resulting in various amino-acid substituent's at Arginine132 (IDH1 R132)-a key residue found in the enzyme's active site that when mutated results in the loss-of-function in metabolizing isocitrate but confers a gain-of-function to produce the oncometabolite 2-hydroxyglutarate (2HG). This in effect defines IDH1 as an oncogene and provides an extraordinary opportunity to discover chemical probes against mutant IDH1 that may translate into much needed new therapies for glioma and AML patients. The proposal has two specific aims: (1) Discovery of novel chemical probes against mutant IDH1 using a validated HTS assay for IDH1 R132H; (2) Performing a synthetic-lethal screen for chemical probes specific for 2HG-producing tumor cells using matched pair cell lines (parental U87MG glioblastoma, and a U87MG stable cell-line that constitutively expresses IDH1R132H mutant). PUBLIC HEALTH RELEVANCE: The aim of this proposal is to screen for chemical inhibitors that are specific for the mutant form of isocitrate dehydrogenase 1 (IDH1). Recently, 70% of grade II-IV gliomas were found to harbor recurrent IDH mutations. Somatic point mutations of IDH1-associated gliomas resulted in various substitution at Arginine 132 (IDH1 R132)-a residue found in the IDH1 active site that confers a gain-of-function when mutated, resulting in the neomorphic production of the oncometabolite 2- hydroxyglutarate (2HG). The assays described in this proposal provide a unique opportunity to identify chemical probes aimed at study the role of mutant IDH1 and 2HG in gliomas.
