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BioAssay: AID 602183

qHTS for Inhibitors of mutant isocitrate dehydrogenase 1 (IDH1): Summary

Unbiased genomic sequencing for 22 glioma genomes found recurrent mutation of isocitrate dehydrogenase 1 (IDH1) on chromosome 2q33-a gene encoding the cytosolic isoform of IIDH1associated with the tricarboxylic acid cycle (TCA) that catalyzes the oxidative decarboxylation of isocitrate, yielding alpha-ketoglutarate and CO2 via NADP+ to NADPH conversion. Subsequent studies confirmed the recurrent more ..
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AID: 602183
Data Source: NCGC (IDH000)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2012-01-12
Target
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AIDNameTypeComment
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623995qHTS for Inhibitors of mutant isocitrate dehydrogenase 1 (IDH1): Cherrypicks in WT IDH1Confirmatorydepositor-specified cross reference
624002qHTS for Inhibitors of mutant isocitrate dehydrogenase 1 (IDH1): Confirmation of CherrypicksConfirmatorydepositor-specified cross reference
624019qHTS for Inhibitors of mutant isocitrate dehydrogenase 1 (IDH1): 2HG production assay for probe SARConfirmatorydepositor-specified cross reference
624021qHTS for Inhibitors of mutant isocitrate dehydrogenase 1 (IDH1): WT assay for probe SARConfirmatorydepositor-specified cross reference
624023qHTS for Inhibitors of mutant isocitrate dehydrogenase 1 (IDH1): confirmation assay for probe SARConfirmatorydepositor-specified cross reference
624059qHTS for Inhibitors of Mutant Isocitrate Dehydrogenase 1 (IDH1): U87 Cytotoxicity Assay for Probe SARConfirmatorydepositor-specified cross reference
624462qHTS for Inhibitors of mutant isocitrate dehydrogenase 1 (IDH1): Aqueous Kinetic SolubilityOtherdepositor-specified cross reference
Description:
Unbiased genomic sequencing for 22 glioma genomes found recurrent mutation of isocitrate dehydrogenase 1 (IDH1) on chromosome 2q33-a gene encoding the cytosolic isoform of IIDH1associated with the tricarboxylic acid cycle (TCA) that catalyzes the oxidative decarboxylation of isocitrate, yielding alpha-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 substituents 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.

Hence, a HTS-compatible fluorescent, enzymatic assay to identify inhibitors of IDH1 to screen the NIH Molecular Libraries Small Molecule Repository (MLSMR). Follow-up assays are planned to further evaluate hits.

NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Centers Network [MLPCN]

MLPCN Grant: DA032129
Assay Submitter (PI): Lenny Dang, Agios Pharmaceuticals
Protocol
Please see linked AIDs for protocol.
Comment
This is project is on-going and will be updated at a later point.
Additional Information
Grant Number: DA032129

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