Drug repurposing: progress, challenges and recommendations

Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.

[1]  W. Young,et al.  Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women. , 1991, Endocrinology.

[2]  K. Maclennan,et al.  Remission of inflammatory arthropathy in association with anti-CD20 therapy for non-Hodgkin's lymphoma. , 1999, Rheumatology.

[3]  Philip R. Cohen,et al.  Use of a drug‐resistant mutant of stress‐activated protein kinase 2a/p38 to validate the in vivo specificity of SB 203580 , 1999, FEBS letters.

[4]  Philip R. Cohen,et al.  Paradoxical activation of Raf by a novel Raf inhibitor. , 1999, Chemistry & biology.

[5]  B. Barlogie,et al.  Antitumor activity of thalidomide in refractory multiple myeloma. , 1999, The New England journal of medicine.

[6]  C. Isaacs,et al.  Hot flushes , 2002, The Lancet.

[7]  M. Somerville.  A postmodern moral tale: the ethics of research relationships , 2002, Nature Reviews Drug Discovery.

[8]  P. Cohen.  Protein kinases — the major drug targets of the twenty-first century? , 2002, Nature reviews. Drug discovery.

[9]  J. Kuriyan,et al.  Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases. , 2002, Cancer research.

[10]  T. Ashburn,et al.  Drug repositioning: identifying and developing new uses for existing drugs , 2004, Nature Reviews Drug Discovery.

[11]  J. Bajorath,et al.  Docking and scoring in virtual screening for drug discovery: methods and applications , 2004, Nature Reviews Drug Discovery.

[12]  William Pao,et al.  Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  György Kéri,et al.  Cellular targets of gefitinib. , 2005, Cancer research.

[14]  S. Evangelista.  Talnetant GlaxoSmithKline. , 2005, Current opinion in investigational drugs.

[15]  H. Tilg,et al.  The RANKL/OPG system is activated in inflammatory bowel disease and relates to the state of bone loss , 2005, Gut.

[16]  F. Sharp,et al.  Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801 , 2006, Neuropsychopharmacology.

[17]  Paul A Clemons,et al.  The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease , 2006, Science.

[18]  T. Golub,et al.  Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. , 2006, Cancer cell.

[19]  T. Golub,et al.  Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. , 2006, Cancer cell.

[20]  L. Otterbein,et al.  N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. , 2006, Journal of medicinal chemistry.

[21]  C. E. Peishoff,et al.  A critical assessment of docking programs and scoring functions. , 2006, Journal of medicinal chemistry.

[22]  Tudor I. Oprea,et al.  Systems chemical biology. , 2007 .

[23]  J. Fletcher,et al.  Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  P. Bork,et al.  Drug Target Identification Using Side-Effect Similarity , 2008, Science.

[25]  Mindy I. Davis,et al.  A quantitative analysis of kinase inhibitor selectivity , 2008, Nature Biotechnology.

[26]  B. Leber,et al.  Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. , 2009, Blood.

[27]  A. Chiang,et al.  Systematic Evaluation of Drug–Disease Relationships to Identify Leads for Novel Drug Uses , 2009, Clinical pharmacology and therapeutics.

[28]  O. Kallioniemi,et al.  High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth , 2009, Clinical Cancer Research.

[29]  Shu-Dong Zhang,et al.  sscMap: An extensible Java application for connecting small-molecule drugs using gene-expression signatures , 2009, BMC Bioinformatics.

[30]  Michael J. Keiser,et al.  Predicting new molecular targets for known drugs , 2009, Nature.

[31]  R. Tagliaferri,et al.  Discovery of drug mode of action and drug repositioning from transcriptional responses , 2010, Proceedings of the National Academy of Sciences.

[32]  D. di Bernardo,et al.  Identification of small molecules enhancing autophagic function from drug network analysis. , 2010, Autophagy.

[33]  I. Bezprozvanny.  The rise and fall of Dimebon. , 2010, Drug News and Perspectives.

[34]  Clive S Mason,et al.  Drug-resistant aurora A mutants for cellular target validation of the small molecule kinase inhibitors MLN8054 and MLN8237. , 2010, ACS chemical biology.

[35]  Tariq Ahmad,et al.  Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci , 2010, Nature Genetics.

[36]  Volker Brinkmann,et al.  Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis , 2010, Nature Reviews Drug Discovery.

[37]  Francesco Iorio,et al.  Identification of small molecules enhancing autophagic function from drug network analysis , 2010 .

[38]  Pankaj Agarwal,et al.  Systematic Drug Repositioning Based on Clinical Side-Effects , 2011, PloS one.

[39]  Joel Dudley,et al.  Exploiting drug-disease relationships for computational drug repositioning , 2011, Briefings Bioinform..

[40]  M. Massagli,et al.  Accelerated clinical discovery using self-reported patient data collected online and a patient-matching algorithm , 2011, Nature Biotechnology.

[41]  R. Collins,et al.  China Kadoorie Biobank of 0.5 million people: survey methods, baseline characteristics and long-term follow-up. , 2011, International journal of epidemiology.

[42]  R. Shields,et al.  mRNA Expression Signatures of Human Skeletal Muscle Atrophy Identify a Natural Compound that Increases Muscle Mass , 2011, Cell metabolism.

[43]  Kui Xu,et al.  Database identifies FDA-approved drugs with potential to be repurposed for treatment of orphan diseases , 2011, Briefings Bioinform..

[44]  Alexander A. Morgan,et al.  Computational Repositioning of the Anticonvulsant Topiramate for Inflammatory Bowel Disease , 2011, Science Translational Medicine.

[45]  Mindy I. Davis,et al.  Comprehensive analysis of kinase inhibitor selectivity , 2011, Nature Biotechnology.

[46]  Alexander A. Morgan,et al.  Discovery and Preclinical Validation of Drug Indications Using Compendia of Public Gene Expression Data , 2011, Science Translational Medicine.

[47]  R. Shen,et al.  Phase II study of saracatinib (AZD0530) for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). , 2011, Anticancer research.

[48]  F. Pammolli,et al.  The productivity crisis in pharmaceutical R&D , 2011, Nature Reviews Drug Discovery.

[49]  N. Rance,et al.  Activation of neurokinin 3 receptors in the median preoptic nucleus decreases core temperature in the rat. , 2011, Endocrinology.

[50]  Oakland J. Peters,et al.  Predicting new indications for approved drugs using a proteochemometric method. , 2012, Journal of medicinal chemistry.

[51]  T. Karrison,et al.  Phase II study of the Src kinase inhibitor saracatinib (AZD0530) in metastatic melanoma , 2013, Investigational New Drugs.

[52]  Adam A. Margolin,et al.  The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity , 2012, Nature.

[53]  Malorye Allison,et al.  NCATS launches drug repurposing program , 2012, Nature Biotechnology.

[54]  Michal Magid-Slav,et al.  Identification of Common Biological Pathways and Drug Targets Across Multiple Respiratory Viruses Based on Human Host Gene Expression Analysis , 2012, PloS one.

[55]  L. Cardon,et al.  Use of genome-wide association studies for drug repositioning , 2012, Nature Biotechnology.

[56]  S. Brunak,et al.  Mining electronic health records: towards better research applications and clinical care , 2012, Nature Reviews Genetics.

[57]  Julio Saez-Rodriguez,et al.  Network based elucidation of drug response: from modulators to targets , 2013, BMC Systems Biology.

[58]  David Cavalla,et al.  Retrospective clinical analysis for drug rescue: for new indications or stratified patient groups. , 2012, Drug discovery today.

[59]  K. Flaherty,et al.  RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. , 2012, The New England journal of medicine.

[60]  J. Weinstein.  Drug discovery: Cell lines battle cancer , 2012, Nature.

[61]  N. Rance,et al.  Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature , 2012, Proceedings of the National Academy of Sciences.

[62]  Jian Jin,et al.  Dynamic Reprogramming of the Kinome in Response to Targeted MEK Inhibition in Triple-Negative Breast Cancer , 2012, Cell.

[63]  G. Griebel,et al.  Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases? , 2012, Pharmacology & therapeutics.

[64]  J. Scannell,et al.  Diagnosing the decline in pharmaceutical R&D efficiency , 2012, Nature Reviews Drug Discovery.

[65]  F. Iorio,et al.  Transcriptional data: a new gateway to drug repositioning? , 2013, Drug discovery today.

[66]  H. Hara,et al.  Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis , 2013, British journal of pharmacology.

[67]  P. Nordlund,et al.  Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay , 2013, Science.

[68]  Yan Zhao,et al.  Drug repositioning: a machine-learning approach through data integration , 2013, Journal of Cheminformatics.

[69]  Hong-yu Zhang,et al.  Rational drug repositioning by medical genetics , 2013, Nature Biotechnology.

[70]  P. Sanseau,et al.  Computational Drug Repositioning: From Data to Therapeutics , 2013, Clinical pharmacology and therapeutics.

[71]  Julio Saez-Rodriguez,et al.  DvD: An R/Cytoscape pipeline for drug repurposing using public repositories of gene expression data , 2012, Bioinform..

[72]  Joshua C. Gilbert,et al.  An Interactive Resource to Identify Cancer Genetic and Lineage Dependencies Targeted by Small Molecules , 2013, Cell.

[73]  Julian Blagg,et al.  A public-private partnership to unlock the untargeted kinome. , 2013, Nature chemical biology.

[74]  Solid-Timi Investigators.  Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. , 2014 .

[75]  Dylan L. Steen,et al.  Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. , 2014, JAMA.

[76]  Susana Murteira,et al.  Drug reformulations and repositioning in the pharmaceutical industry and their impact on market access: regulatory implications , 2014, Journal of market access & health policy.

[77]  M. Sereda,et al.  Rho kinase inhibition modulates microglia activation and improves survival in a model of amyotrophic lateral sclerosis , 2013, Glia.

[78]  David P. Argue,et al.  Larval Zebrafish Model for FDA-Approved Drug Repositioning for Tobacco Dependence Treatment , 2014, PloS one.

[79]  Teemu P. Miettinen,et al.  NQO2 Is a Reactive Oxygen Species Generating Off-Target for Acetaminophen , 2014, Molecular pharmaceutics.

[80]  R. Conwit,et al.  Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial , 2014, The Lancet Neurology.

[81]  Seth D. Crockett,et al.  Topiramate Use Does Not Reduce Flares of Inflammatory Bowel Disease , 2014, Digestive Diseases and Sciences.

[82]  N. Eissa,et al.  SRC kinase is a novel therapeutic target in lymphangioleiomyomatosis. , 2014, Cancer research.

[83]  U. Storz.  Rituximab , 2014, Reactions Weekly.

[84]  U. Storz.  Rituximab: how approval history is reflected by a corresponding patent filing strategy. , 2014, mAbs.

[85]  Sona Warrier,et al.  Reverse docking: a powerful tool for drug repositioning and drug rescue. , 2014, Future medicinal chemistry.

[86]  T. Willson,et al.  Seeding Collaborations to Advance Kinase Science with the GSK Published Kinase Inhibitor Set (PKIS) , 2014, Current topics in medicinal chemistry.

[87]  P. Pais,et al.  Darapladib for preventing ischemic events in stable coronary heart disease. , 2014, The New England journal of medicine.

[88]  R. M. Owen,et al.  An analysis of the attrition of drug candidates from four major pharmaceutical companies , 2015, Nature Reviews Drug Discovery.

[89]  Atul J. Butte,et al.  Repurpose terbutaline sulfate for amyotrophic lateral sclerosis using electronic medical records , 2015, Scientific Reports.

[90]  Sara Ballouz,et al.  Novel therapeutics for coronary artery disease from genome-wide association study data , 2015, BMC Medical Genomics.

[91]  Ji Eun Lee,et al.  Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis. , 2015, Biochimica et biophysica acta.

[92]  Michael Eisenstein,et al.  Big data: The power of petabytes , 2015, Nature.

[93]  Kewei Chen,et al.  A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer’s disease , 2015, Alzheimer's Research & Therapy.

[94]  E. Ruppin,et al.  Drugs that reverse disease transcriptomic signatures are more effective in a mouse model of dyslipidemia , 2015 .

[95]  A. Luini,et al.  Unravelling druggable signalling networks that control F508del-CFTR proteostasis , 2015, eLife.

[96]  M. Zizzo,et al.  GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation. , 2015, Pharmacological research.

[97]  M. Ritchie,et al.  Methods of integrating data to uncover genotype–phenotype interactions , 2015, Nature Reviews Genetics.

[98]  Julio Saez-Rodriguez,et al.  A Semi-Supervised Approach for Refining Transcriptional Signatures of Drug Response and Repositioning Predictions , 2015, PloS one.

[99]  Jonathan S. Mason,et al.  Structures of G protein-coupled receptors reveal new opportunities for drug discovery. , 2015, Drug discovery today.

[100]  E. Ruppin,et al.  Drugs that reverse disease transcriptomic signatures are more effective in a mouse model of dyslipidemia , 2015, Molecular systems biology.

[101]  J. Denny,et al.  Extracting research-quality phenotypes from electronic health records to support precision medicine , 2015, Genome Medicine.

[102]  S. Bloom,et al.  Neurokinin B Administration Induces Hot Flushes in Women , 2015, Scientific Reports.

[103]  S. Strittmatter,et al.  Fyn inhibition rescues established memory and synapse loss in Alzheimer mice , 2015, Annals of neurology.

[104]  Daniel S. Himmelstein,et al.  Understanding multicellular function and disease with human tissue-specific networks , 2015, Nature Genetics.

[105]  M. Pangalos,et al.  Pioneering government-sponsored drug repositioning collaborations: progress and learning , 2015, Nature Reviews Drug Discovery.

[106]  So Ri Kim,et al.  Drug Signature-based Finding of Additional Clinical Use of LC28-0126 for Neutrophilic Bronchial Asthma , 2015, Scientific Reports.

[107]  F. Collins,et al.  A new initiative on precision medicine. , 2015, The New England journal of medicine.

[108]  Joshua A. Bittker,et al.  Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset. , 2015, Cancer discovery.

[109]  M. Peplow.  The 100 000 Genomes Project , 2016, British Medical Journal.

[110]  B. Voight,et al.  Pathway and network-based strategies to translate genetic discoveries into effective therapies , 2016, bioRxiv.

[111]  Y-Y Hsieh,et al.  Repositioning of a cyclin-dependent kinase inhibitor GW8510 as a ribonucleotide reductase M2 inhibitor to treat human colorectal cancer , 2016, Cell Death Discovery.

[112]  Nicola Nosengo.  Can you teach old drugs new tricks? , 2016, Nature.

[113]  Emanuel J. V. Gonçalves,et al.  A Landscape of Pharmacogenomic Interactions in Cancer , 2016, Cell.

[114]  R. Lai,et al.  The use of cellular thermal shift assay (CETSA) to study Crizotinib resistance in ALK-expressing human cancers , 2016, Scientific Reports.

[115]  C. Vakoc,et al.  A Biomarker Harvest from One Thousand Cancer Cell Lines , 2016, Cell.

[116]  Ying Chen,et al.  IBM Watson: How Cognitive Computing Can Be Applied to Big Data Challenges in Life Sciences Research. , 2016, Clinical therapeutics.

[117]  John P. Overington,et al.  Comprehensive characterization of the Published Kinase Inhibitor Set , 2016, Nature Biotechnology.

[118]  Natasa Przulj,et al.  Integrative methods for analyzing big data in precision medicine , 2016, Proteomics.

[119]  David Cyranoski,et al.  China embraces precision medicine on a massive scale , 2016, Nature.

[120]  R. Collins,et al.  A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults , 2016, International Journal of Epidemiology.

[121]  J. Baselga,et al.  The hVps34‐SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth , 2016, The EMBO journal.

[122]  Ruili Huang,et al.  Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen , 2016, Nature Medicine.

[123]  G. Drewes,et al.  Discovery of Novel Small Molecules that Activate Satellite Cell Proliferation and Enhance Repair of Damaged Muscle. , 2016, ACS chemical biology.

[124]  Kathleen M Jagodnik,et al.  Extraction and analysis of signatures from the Gene Expression Omnibus by the crowd , 2016, Nature Communications.

[125]  Robert Preissner,et al.  Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors. , 2016, ACS chemical biology.

[126]  J. Tuszynski,et al.  Software for molecular docking: a review , 2017, Biophysical Reviews.

[127]  Madeleine Ennis,et al.  Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis , 2016, Proceedings of the National Academy of Sciences.

[128]  M. Fallahi,et al.  Crizotinib inhibits NF2-associated schwannoma through inhibition of focal adhesion kinase 1 , 2016, Oncotarget.

[129]  I. Holen,et al.  Effects of Src-kinase inhibition in cancer-induced bone pain , 2016, Molecular pain.

[130]  Chi-Ying F. Huang,et al.  Identify potential drugs for cardiovascular diseases caused by stress-induced genes in vascular smooth muscle cells , 2016, PeerJ.

[131]  Noel Southall,et al.  Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria , 2016, Emerging microbes & infections.

[132]  Lenka Munoz,et al.  Non-kinase targets of protein kinase inhibitors , 2017, Nature Reviews Drug Discovery.

[133]  M. Pirmohamed,et al.  Genetic regulation of gene expression in the epileptic human hippocampus , 2017, Human molecular genetics.

[134]  W. Dhillo,et al.  Neurokinin 3 receptor antagonism – the magic bullet for hot flushes? , 2017, Climacteric : the journal of the International Menopause Society.

[135]  N. Ives,et al.  Assessing the Efficacy and Safety of an 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor (AZD4017) in the Idiopathic Intracranial Hypertension Drug Trial, IIH:DT: Clinical Methods and Design for a Phase II Randomized Controlled Trial , 2017, JMIR research protocols.

[136]  D. Timmerman,et al.  Clinical evaluation of the NK3 receptor antagonist fezolinetant (a.k.a. ESN364) for the treatment of menopausal hot flashes , 2017 .

[137]  Munir Pirmohamed,et al.  Identifying new antiepileptic drugs through genomics‐based drug repurposing , 2017, Human molecular genetics.

[138]  L. Huson,et al.  Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial , 2017, The Lancet.

[139]  Julian Blagg,et al.  Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology , 2017, Cancer cell.

[140]  Megan Cully.  Deal watch: Neurokinin 3 receptor antagonist revival heats up with Astellas acquisition , 2017, Nature Reviews Drug Discovery.

[141]  M. Prunotto,et al.  Opportunities and challenges in phenotypic drug discovery: an industry perspective , 2017, Nature Reviews Drug Discovery.

[142]  S. Horvath,et al.  Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women's Health Initiative Study , 2017, Menopause.

[143]  Jian Peng,et al.  A Network Integration Approach for Drug-Target Interaction Prediction and Computational Drug Repositioning from Heterogeneous Information , 2017, RECOMB 2017.

[144]  Jian Peng,et al.  A network integration approach for drug-target interaction prediction and computational drug repositioning from heterogeneous information , 2017, Nature Communications.

[145]  M. Sereda,et al.  Rho Kinase Inhibition with Fasudil in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis—Symptomatic Treatment Potential after Disease Onset , 2017, Front. Pharmacol..

[146]  Cassandra Willyard.  New human gene tally reignites debate , 2018, Nature.

[147]  Hongbin Huang,et al.  Reverse Screening Methods to Search for the Protein Targets of Chemopreventive Compounds , 2018, Front. Chem..

[148]  Alasdair Breckenridge,et al.  Overcoming the legal and regulatory barriers to drug repurposing , 2018, Nature Reviews Drug Discovery.

[149]  Laureline Berteloot,et al.  Targeted therapy in patients with PIK3CA-related overgrowth syndrome , 2018, Nature.

[150]  Dejan Juric,et al.  Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[151]  Lisa Urquhart,et al.  Market watch: Top drugs and companies by sales in 2017 , 2018, Nature Reviews Drug Discovery.