Next Article in Journal
Retraction: Zhao et al. Protective Effect of Glycyrrhizic Acid on Alcoholic Liver Injury in Rats by Modulating Lipid Metabolism. Molecules 2018, 23(7), 1623
Next Article in Special Issue
Synthesis of 3-(Imidazo[2,1-b]thiazol-6-yl)-2H-chromen-2-one Derivatives and Study of Their Antiviral Activity against Parvovirus B19
Previous Article in Journal
Optimized Prediction of Reducing Sugars and Dry Matter of Potato Frying by FT-NIR Spectroscopy on Peeled Tubers
Previous Article in Special Issue
Synthesis and AChE-Inhibitory Activity of New Benzimidazole Derivatives
Article Menu
Issue 5 (March-1) cover image

Export Article

Open AccessReview
Molecules 2019, 24(5), 968; https://doi.org/10.3390/molecules24050968

Consequences of IDH1/2 Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins

1
Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 02-093 Warsaw, Poland
2
Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-093 Warsaw, Poland
3
Department of Biochemistry, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, 30-705 Krakow, Poland
4
Department of Neurosurgery, Mazovian Bródnowski Hospital, 03-242 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Academic Editor: Silvia Schenone
Received: 3 February 2019 / Revised: 1 March 2019 / Accepted: 4 March 2019 / Published: 9 March 2019
(This article belongs to the Special Issue Medicinal Chemistry in Europe)
Full-Text   |   PDF [652 KB, uploaded 9 March 2019]   |  
  |   Review Reports

Abstract

Isocitrate dehydrogenases (IDH) 1 and 2 are key metabolic enzymes that generate reduced nicotinamide adenine dinucleotide phosphate (NADPH) to maintain a pool of reduced glutathione and peroxiredoxin, and produce α-ketoglutarate, a co-factor of numerous enzymes. IDH1/2 is mutated in ~70–80% of lower-grade gliomas and the majority of secondary glioblastomas. The mutant IDH1 (R132H), in addition to losing its normal catalytic activity, gains the function of producing the d-(R)-2-hydroxyglutarate (2-HG). Overproduction of 2-HG in cancer cells interferes with cellular metabolism and inhibits histone and DNA demethylases, which results in histone and DNA hypermethylation and the blockade of cellular differentiation. We summarize recent findings characterizing molecular mechanisms underlying oncogenic alterations associated with mutated IDH1/2, and their impact on tumor microenvironment and antitumor immunity. Isoform-selective IDH inhibitors which suppress 2-HG production and induce antitumor responses in cells with IDH1 and IDH2 mutations were developed and validated in preclinical settings. Inhibitors of mutated IDH1/2 enzymes entered clinical trials and represent a novel drug class for targeted therapy of gliomas. We describe the development of small-molecule compounds and peptide vaccines targeting IDH-mutant gliomas and the results of their testing in preclinical and clinical studies. All those results support the translational potential of strategies targeting gliomas carrying IDH1 mutations. View Full-Text
Keywords: IDH mutations; metabolic disturbances; epigenetics; gliomas; tumor microenvironment; IHD mutant inhibitors IDH mutations; metabolic disturbances; epigenetics; gliomas; tumor microenvironment; IHD mutant inhibitors
Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
SciFeed

Share & Cite This Article

MDPI and ACS Style

Kaminska, B.; Czapski, B.; Guzik, R.; Król, S.K.; Gielniewski, B. Consequences of IDH1/2 Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins. Molecules 2019, 24, 968.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top