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      Overcoming Obstacles to Drug Repositioning in Japan

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          Abstract

          Drug repositioning (DR) is the process of identifying new indications for existing drugs. DR usually focuses on drugs that have cleared phase-I safety trials but has yet to show efficacy for the intended indication. Therefore, DR can probably skip the preclinical and phase-I study, which can reduce the cost throughout drug development. However, the expensive phase-II/III trials are required to establish efficacy. The obstacles to DR include identification of new indications with a high success rate in clinical studies, obtaining funding for clinical studies, patent protection, and approval systems. To tackle these obstacles, various approaches have been applied to DR worldwide. In this perspective, we provide representative examples of DR and discuss the ongoing efforts to overcome obstacles to DR in Japan.

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          Most cited references38

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          druGAN: An Advanced Generative Adversarial Autoencoder Model for de Novo Generation of New Molecules with Desired Molecular Properties in Silico.

          Deep generative adversarial networks (GANs) are the emerging technology in drug discovery and biomarker development. In our recent work, we demonstrated a proof-of-concept of implementing deep generative adversarial autoencoder (AAE) to identify new molecular fingerprints with predefined anticancer properties. Another popular generative model is the variational autoencoder (VAE), which is based on deep neural architectures. In this work, we developed an advanced AAE model for molecular feature extraction problems, and demonstrated its advantages compared to VAE in terms of (a) adjustability in generating molecular fingerprints; (b) capacity of processing very large molecular data sets; and (c) efficiency in unsupervised pretraining for regression model. Our results suggest that the proposed AAE model significantly enhances the capacity and efficiency of development of the new molecules with specific anticancer properties using the deep generative models.
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            LINCS Canvas Browser: interactive web app to query, browse and interrogate LINCS L1000 gene expression signatures

            For the Library of Integrated Network-based Cellular Signatures (LINCS) project many gene expression signatures using the L1000 technology have been produced. The L1000 technology is a cost-effective method to profile gene expression in large scale. LINCS Canvas Browser (LCB) is an interactive HTML5 web-based software application that facilitates querying, browsing and interrogating many of the currently available LINCS L1000 data. LCB implements two compacted layered canvases, one to visualize clustered L1000 expression data, and the other to display enrichment analysis results using 30 different gene set libraries. Clicking on an experimental condition highlights gene-sets enriched for the differentially expressed genes from the selected experiment. A search interface allows users to input gene lists and query them against over 100 000 conditions to find the top matching experiments. The tool integrates many resources for an unprecedented potential for new discoveries in systems biology and systems pharmacology. The LCB application is available at http://www.maayanlab.net/LINCS/LCB. Customized versions will be made part of the http://lincscloud.org and http://lincs.hms.harvard.edu websites.
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              The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis

              Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72. Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                11 October 2017
                2017
                : 8
                : 729
                Affiliations
                [1] 1Department of Integrative Pharmacology, Mie University Graduate School of Medicine , Tsu, Japan
                [2] 2Medical Affairs, Sumitomo Dainippon Pharma Co., Ltd. , Tokyo, Japan
                [3] 3Department of CNS Research, Otsuka Pharmaceutical Co., Ltd. , Tokushima, Japan
                [4] 4Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University , Gifu, Japan
                Author notes

                Edited by: Luc Zimmer, Université Claude Bernard Lyon 1 and Hospices Civils de Lyon, France

                Reviewed by: Afzal Chowdhury, Perkins Coie, LLP, United States; Aris Persidis, Biovista, United States

                *Correspondence: Yuhei Nishimura, yuhei@ 123456doc.medic.mie-u.ac.jp

                This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2017.00729
                5641581
                7886b457-aa76-4c30-80ee-08fc0ee74fed
                Copyright © 2017 Nishimura, Tagawa, Ito, Tsuruma and Hara.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 26 July 2017
                : 28 September 2017
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 53, Pages: 6, Words: 0
                Categories
                Pharmacology
                Perspective

                Pharmacology & Pharmaceutical medicine
                industry-sponsored clinical trial,investigator-initiated clinical trial,electronic health record,sharing resources,computational drug repositioning

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