Novel Insights for Inhibiting Mutant Heterodimer IDH1 wt-R132H in Cancer: An In-Silico Approach
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ORIGINAL RESEARCH ARTICLE
Novel Insights for Inhibiting Mutant Heterodimer IDH1wt-R132H in Cancer: An In-Silico Approach Ezequiel Iva´n Juritz1 • Juan Pablo Bascur1 • Daniel Eduardo Almonacid1,2 Fernando Danilo Gonza´lez-Nilo1,3
•
Ó Springer International Publishing AG, part of Springer Nature 2018
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.
Key Points We describe a novel bioinformatics approach to inhibit isocitrate dehydrogenase 1 (IDH1) variant enzymes. We performed a virtual screening of all US FDAapproved drugs to find potential inhibitors of the heterodimeric IDH1 R132H mutant enzyme. We found 20 drugs with potential inhibiting properties for heterodimeric IDH1; six are used in cancer therapy and one presents enhanced activity in patients with IDH1 mutations.
& Ezequiel Iva´n Juritz [email protected] 1
Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andre´s Bello, 8370146 Santiago, Chile
2
uBiome, Inc., San Francisco, CA, USA
3
Centro Interdisciplinario de Neurociencia de Valparaı´so, Facultad de Ciencias, Universidad de Valparaı´so, 2366103 Valparaı´so, Chile
1 Introduction In humans, three enzymes have isocitrate dehydrogenase (IDH) activity: IDH1, IDH2, and the IDH3 complex [1], which is comprised of the IDH3a, IDH3b, and IDH3g subunits [2]. These enzymes transform isocitrate (ICT) into
E. I. Juritz et al.
a-ketoglutarate (AKG), releasing CO2 an
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