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Isocitrate dehydrogenase variants in cancer - Cellular consequences and therapeutic opportunities.

Authors
  • Liu, Shuang1
  • Cadoux-Hudson, Tom1
  • Schofield, Christopher J2
  • 1 Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
  • 2 Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. Electronic address: [email protected]
Type
Published Article
Journal
Current opinion in chemical biology
Publication Date
Aug 07, 2020
Volume
57
Pages
122–134
Identifiers
DOI: 10.1016/j.cbpa.2020.06.012
PMID: 32777735
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Abnormal metabolism is common in cancer cells and often correlates with mutations in genes encoding for enzymes involved in small-molecule metabolism. Isocitrate dehydrogenase 1 (IDH1) is the most frequently mutated metabolic gene in cancer. Cancer-associated substitutions in IDH1 and IDH2 impair wild-type production of 2-oxoglutarate and reduced nicotinamide adenine dinucleotide phosphate (NADPH) from isocitrate and oxidised nicotinamide adenine dinucleotide phosphate (NADP+ ), and substantially promote the IDH variant catalysed conversion of 2-oxoglutarate to d-2-hydroxyglutarate (d-2HG). Elevated d-2HG is a biomarker for some cancers, and inhibition of IDH1 and IDH2 variants is being pursued as a medicinal chemistry target. We provide an overview of the types of cancer-associated IDH variants, discuss some of the proposed consequences of altered metabolism as a result of elevated d-2HG, summarise therapeutic efforts targeting IDH variants and identify areas for future research. Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

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