Ezequiel Iván Juritz1, Juan Pablo Bascur2, Daniel Eduardo Almonacid2,3, Fernando Danilo González-Nilo2,4. 1. Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andrés Bello, 8370146, Santiago, Chile. ejuritz@gmail.com. 2. Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andrés Bello, 8370146, Santiago, Chile. 3. uBiome, Inc., San Francisco, CA, USA. 4. Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, 2366103, Valparaíso, Chile.
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.
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.
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