Novel Insights for Inhibiting Mutant Heterodimer IDH1wt-R132H in Cancer: An In-Silico Approach

  • Ezequiel Iván Juritz
  • Juan Pablo Bascur
  • Daniel Eduardo Almonacid
  • Fernando Danilo González-Nilo
Original Research Article
  • 13 Downloads

Abstract

Background

Isocitrate dehydrogenase 1 (IDH1) is a dimeric enzyme responsible for supplying the cell’s nicotinamide adenine dinucleotide phosphate (NADPH) reserves via dehydrogenation of isocitrate (ICT) and reduction of NADP+. Mutations in position R132 trigger cancer by enabling IDH1 to produce d-2-hydroxyglutarate (2-HG) and reduce inhibition by ICT. Mutant IDH1 can be found as a homodimer or a heterodimer.

Objective

We propose a novel strategy to inhibit IDH1 R132 variants as a means not to decrease the concentration of 2-HG but to provoke a cytotoxic effect, as the cell malignancy at this point no longer depends on 2-HG. We aim to inhibit the activity of the mutant heterodimer to block the wild-type subunit. Limiting the NADPH reserves in a cancerous cell will enhance its susceptibility to the oxidative stress provoked by chemotherapy.

Methods

We performed a virtual screening using all US FDA-approved drugs to replicate the loss of inhibition of mutant IDH1 by ICT. We characterized our results based on molecular interactions and correlated them with the described phenotypes.

Results

We replicated the loss of inhibition by ICT in mutant IDH1. We identified 20 drugs with the potential to inhibit the heterodimeric isoform. Six of them are used in cancer treatment.

Conclusions

We present 20 FDA-approved drugs with the potential to inhibit IDH1 wild-type activity in mutated cells. We believe this work may provide important insights into current and new approaches to dealing with IDH1 mutations. In addition, it may be used as a basis for additional studies centered on drugs presenting differential sensitivities to different IDH1 isoforms.

Notes

Acknowledgements

The authors wish to thank Dr. Elisabeth Bik for her help improving the manuscript. FDGN thanks to Centro Interdisciplinario de Neurociencia de Valparaíso (CINV) which is a Millennium Institute supported by the Millennium Scientific Initiative of the Ministerio de Economía, Fomento y Turismo, Chile.

Compliance with Ethical Standards

Conflict of interest

The authors EIJ, JPB, DEA and FDGN have no conflicts of interest that are directly relevant to the content of this study. DEA is currently an employee of uBiome, Inc. and has received stock options as well as other compensations. FDGN is currently an advisor to uBiome, Inc. and has received stock options. uBiome had no influence on the design or execution of this study.

Funding

This study was funded by FONDECYT postdoctoral Grant no. 3150671 (PI: EIJ) and FONDECYT Proyecto de Inicio no. 11130578 (PI: DEA).

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Ezequiel Iván Juritz
    • 1
  • Juan Pablo Bascur
    • 1
  • Daniel Eduardo Almonacid
    • 1
    • 2
  • Fernando Danilo González-Nilo
    • 1
    • 3
  1. 1.Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la VidaUniversidad Andrés BelloSantiagoChile
  2. 2.uBiome, Inc.San FranciscoUSA
  3. 3.Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de CienciasUniversidad de ValparaísoValparaísoChile

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