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BioAssay: AID 686972

qHTS for inhibitors of synthetic-lethal in tumor cells producing 2HG: Summary

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 alpha-ketoglutarate and CO2 via NADP+ to NADPH conversion. Subsequent studies confirmed the recurrent IDH mutations in up to 70% more ..
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AID: 686972
Data Source: NCGC (IDH1-lethal-summary)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2013-05-06
Modify Date: 2013-05-09
Target
Related Experiments
AIDNameTypeComment
686970qHTS for induction of synthetic lethality in tumor cells producing 2HG: qHTS for the HT-1080-NT fibrosarcoma cell lineConfirmatorydepositor-specified cross reference
686971qHTS for induction of synthetic lethality in tumor cells producing 2HG: qHTS for the HT-1080-IDH1KD cell lineConfirmatorydepositor-specified cross reference
Description:
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 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 [1]. In addition, 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 onco-metabolite 2-hydroxyglutarate (2HG) [2]. 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.
This assay aims to perform a synthetic-lethal screen for chemical probes specific for 2HG-producing tumor cells using matched paired cell lines (1) HT-1080 fibrosarcoma cell line that overproduces 2HG and (2) HT-1080-IDH1KD cell line which has IDH1 expression knocked-down. The data in this AID corresponds to the results of the qHTS against the HT-1080 fibrosarcoma cell line.

[1] Dang L, Jin S, Su SM. IDH mutations in glioma and acute myeloid leukemia. Trends of Mol Med. 2010; 16(9): 387-97.
[2] Dang L et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2010; 465(7300):966.

NIH Molecular Libraries Probe Production Centers Network [MLPCN]
NIH Chemical Genomics Center [NCGC]
MLPCN Grant: DA032129
Assay Submitter (PI): Lenny Dang Ph.D., Agios Pharmaceuticals
Protocol
Please refer to the linked AIDs for detailed protocols
Additional Information
Grant Number: DA032129

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