{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:16:01Z","timestamp":1772172961205,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009302","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000}}],"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T00:00:00Z","timestamp":1631577600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54OD020353"],"award-info":[{"award-number":["U54OD020353"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM131881"],"award-info":[{"award-number":["R35GM131881"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>A continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple reasons including lack of efficacy, rapidly acquired drug resistance, and narrow patient eligibility criteria. An alternative approach is the development of drugs that address the overall disease network by targeting multiple biological targets (\u2018polypharmacology\u2019). Rational development of these molecules will require improved methods for predicting single chemical structures that target multiple drug targets. To address this need, we developed the Multi-Targeting Drug DREAM Challenge, in which we challenged participants to predict single chemical entities that target pro-targets but avoid anti-targets for two unrelated diseases: RET-based tumors and a common form of inherited Tauopathy. Here, we report the results of this DREAM Challenge and the development of two neural network-based machine learning approaches that were applied to the challenge of rational polypharmacology. Together, these platforms provide a potentially useful first step towards developing lead therapeutic compounds that address disease complexity through rational polypharmacology.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009302","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T13:31:20Z","timestamp":1631626280000},"page":"e1009302","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5041-9385","authenticated-orcid":true,"given":"Zhaoping","family":"Xiong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-6186","authenticated-orcid":true,"given":"Minji","family":"Jeon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3573-3565","authenticated-orcid":true,"given":"Robert J.","family":"Allaway","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6798-9106","authenticated-orcid":true,"given":"Jaewoo","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2762-3737","authenticated-orcid":true,"given":"Donghyeon","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4972-239X","authenticated-orcid":true,"given":"Jinhyuk","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hwisang","family":"Jeon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miyoung","family":"Ko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hualiang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyue","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2955-8369","authenticated-orcid":true,"given":"Aik Choon","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0479-4317","authenticated-orcid":true,"given":"Xindi","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"The Multi-Targeting Drug DREAM Challenge Community","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristen K.","family":"Dang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Tropsha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chana","family":"Hecht","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tirtha K.","family":"Das","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7495-1699","authenticated-orcid":true,"given":"Heather A.","family":"Carlson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9309-2976","authenticated-orcid":true,"given":"Ruben","family":"Abagyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1477-1888","authenticated-orcid":true,"given":"Justin","family":"Guinney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4007-7814","authenticated-orcid":true,"given":"Avner","family":"Schlessinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ross","family":"Cagan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,9,14]]},"reference":[{"key":"pcbi.1009302.ref001","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.drudis.2015.09.010","article-title":"A new paradigm for navigating compound property related drug attrition","author":"P Barton","year":"2016","journal-title":"Drug Discovery Today"},{"key":"pcbi.1009302.ref002","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-662-43914-2","volume-title":"Reducing Drug Attrition","author":"JR Empfield","year":"2014"},{"key":"pcbi.1009302.ref003","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1016\/j.ejca.2012.11.019","article-title":"Resistance to BRAF-targeted therapy in melanoma","volume":"49","author":"RJ Sullivan","year":"2013","journal-title":"Eur J Cancer"},{"key":"pcbi.1009302.ref004","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1001\/jamaoncol.2018.1660","article-title":"Estimation of the Percentage of US Patients With Cancer Who Benefit From Genome-Driven Oncology","volume":"4","author":"J Marquart","year":"2018","journal-title":"JAMA Oncol"},{"key":"pcbi.1009302.ref005","article-title":"Probing the chemical\u2013biological relationship space with the Drug Target Explorer","author":"RJ Allaway","year":"2018","journal-title":"Journal of Cheminformatics"},{"key":"pcbi.1009302.ref006","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1021\/acs.jcim.9b00031","article-title":"Extended Multitarget Pharmacology of Anticancer Drugs","volume":"59","author":"D Shi","year":"2019","journal-title":"J Chem Inf Model"},{"key":"pcbi.1009302.ref007","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1038\/nbt.1990","article-title":"Comprehensive analysis of kinase inhibitor selectivity","volume":"29","author":"MI Davis","year":"2011","journal-title":"Nat Biotechnol"},{"key":"pcbi.1009302.ref008","doi-asserted-by":"crossref","first-page":"3538","DOI":"10.1158\/0008-5472.CAN-04-4561","article-title":"ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma","volume":"65","author":"M Vidal","year":"2005","journal-title":"Cancer Res"},{"key":"pcbi.1009302.ref009","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1677\/ERC-09-0292","article-title":"The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells","volume":"18","author":"D Vitagliano","year":"2011","journal-title":"Endocr Relat Cancer"},{"key":"pcbi.1009302.ref010","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1182\/blood-2009-08-237404","article-title":"Dysregulation of bone remodeling by imatinib mesylate","volume":"115","author":"K Vandyke","year":"2010","journal-title":"Blood"},{"key":"pcbi.1009302.ref011","doi-asserted-by":"crossref","first-page":"10010","DOI":"10.1093\/nar\/gkz805","article-title":"Signatures of cell death and proliferation in perturbation transcriptomics data-from confounding factor to effective prediction","volume":"47","author":"B Szalai","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1009302.ref012","article-title":"Crowdsourced mapping of unexplored target space of kinase inhibitors","author":"A Cichonska","year":"2020","journal-title":"bioRxiv."},{"key":"pcbi.1009302.ref013","doi-asserted-by":"crossref","first-page":"782","DOI":"10.3389\/fchem.2019.00782","article-title":"Comparison Study of Computational Prediction Tools for Drug-Target Binding Affinities","volume":"7","author":"M Thafar","year":"2019","journal-title":"Front Chem"},{"key":"pcbi.1009302.ref014","doi-asserted-by":"crossref","first-page":"e1006651","DOI":"10.1371\/journal.pcbi.1006651","article-title":"Predicting protein targets for drug-like compounds using transcriptomics","volume":"14","author":"NA Pabon","year":"2018","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1009302.ref015","article-title":"A Community Challenge for Pancancer Drug Mechanism of Action Inference from Perturbational Profile Data","author":"EF Douglass","year":"2020","journal-title":"bioRxiv"},{"key":"pcbi.1009302.ref016","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/978-1-4939-9089-4_11","article-title":"Omics Data Integration and Analysis for Systems Pharmacology","volume":"1939","author":"H Lim","year":"2019","journal-title":"Methods Mol Biol"},{"key":"pcbi.1009302.ref017","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/s41573-019-0050-3","article-title":"Rethinking drug design in the artificial intelligence era","volume":"19","author":"P Schneider","year":"2020","journal-title":"Nat Rev Drug Discov"},{"key":"pcbi.1009302.ref018","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1038\/s41587-019-0224-x","article-title":"Deep learning enables rapid identification of potent DDR1 kinase inhibitors","volume":"37","author":"A Zhavoronkov","year":"2019","journal-title":"Nat Biotechnol"},{"key":"pcbi.1009302.ref019","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.chembiol.2018.11.005","article-title":"What Makes a Kinase Promiscuous for Inhibitors?","volume":"26","author":"SM Hanson","year":"2019","journal-title":"Cell Chem Biol"},{"key":"pcbi.1009302.ref020","doi-asserted-by":"crossref","first-page":"D361","DOI":"10.1093\/nar\/gky916","article-title":"KinaMetrix: a web resource to investigate kinase conformations and inhibitor space","volume":"47","author":"R Rahman","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1009302.ref021","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1016\/j.chembiol.2017.12.006","article-title":"Multi-targeting Drug Community Challenge","volume":"24","author":"A Schlessinger","year":"2017","journal-title":"Cell Chem Biol"},{"key":"pcbi.1009302.ref022","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1534\/genetics.104.038018","article-title":"A Drosophila model of multiple endocrine neoplasia type 2","volume":"171","author":"RD Read","year":"2005","journal-title":"Genetics"},{"key":"pcbi.1009302.ref023","article-title":"A whole-animal platform to advance a clinical kinase inhibitor into new disease space","author":"M Sonoshita","year":"2018","journal-title":"Nat Chem Biol"},{"key":"pcbi.1009302.ref024","doi-asserted-by":"crossref","first-page":"eaav6528","DOI":"10.1126\/sciadv.aav6528","article-title":"A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer","volume":"5","author":"E Bangi","year":"2019","journal-title":"Sci Adv"},{"key":"pcbi.1009302.ref025","doi-asserted-by":"crossref","first-page":"102212","DOI":"10.1016\/j.isci.2021.102212","article-title":"A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma","volume":"24","author":"E Bangi","year":"2021","journal-title":"iScience"},{"key":"pcbi.1009302.ref026","doi-asserted-by":"crossref","first-page":"539","DOI":"10.3233\/JAD-130617","article-title":"Expression of Alzheimer-like pathological human tau induces a behavioral motor and olfactory learning deficit in Drosophila melanogaster","volume":"37","author":"C Beharry","year":"2013","journal-title":"J Alzheimers Dis"},{"key":"pcbi.1009302.ref027","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1093\/hmg\/ddm011","article-title":"Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila","volume":"16","author":"O Blard","year":"2007","journal-title":"Hum Mol Genet"},{"key":"pcbi.1009302.ref028","first-page":"39","article-title":"Modelling cell and isoform type specificity of tauopathies in Drosophila","volume":"60","author":"S Grammenoudi","year":"2008","journal-title":"SEB Exp Biol Ser"},{"key":"pcbi.1009302.ref029","article-title":"Grape-seed polyphenolic extract improves the eye phenotype in a Drosophila model of tauopathy","volume":"2010","author":"CM Pfleger","year":"2010","journal-title":"Int J Alzheimers Dis"},{"key":"pcbi.1009302.ref030","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1002\/1096-9861(20001225)428:4<630::AID-CNE4>3.0.CO;2-X","article-title":"Tau and tau reporters disrupt central projections of sensory neurons in Drosophila","volume":"428","author":"DW Williams","year":"2000","journal-title":"J Comp Neurol"},{"key":"pcbi.1009302.ref031","article-title":"Deep Learning Enhancing Kinome-Wide Polypharmacology Profiling: Model Construction and Experiment Validation","author":"X Li","year":"2019","journal-title":"J Med Chem"},{"key":"pcbi.1009302.ref032","article-title":"Pushing the Boundaries of Molecular Representation for Drug Discovery with the Graph Attention Mechanism","author":"Z Xiong","year":"2019","journal-title":"J Med Chem"},{"key":"pcbi.1009302.ref033","doi-asserted-by":"crossref","first-page":"5249","DOI":"10.1093\/bioinformatics\/btz411","article-title":"ReSimNet: drug response similarity prediction using Siamese neural networks","volume":"35","author":"M Jeon","year":"2019","journal-title":"Bioinformatics"},{"key":"pcbi.1009302.ref034","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","article-title":"A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles","volume":"171","author":"A Subramanian","year":"2017","journal-title":"Cell"},{"key":"pcbi.1009302.ref035","article-title":"Adam: A Method for Stochastic Optimization","author":"DP Kingma","year":"2014","journal-title":"arXiv [cs.LG]."},{"key":"pcbi.1009302.ref036","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1021\/acs.jcim.5b00559","article-title":"ZINC 15\u2014Ligand Discovery for Everyone","volume":"55","author":"T Sterling","year":"2015","journal-title":"J Chem Inf Model"},{"key":"pcbi.1009302.ref037","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/nature11127","article-title":"Chemical genetic discovery of targets and anti-targets for cancer polypharmacology","volume":"486","author":"AC Dar","year":"2012","journal-title":"Nature"},{"key":"pcbi.1009302.ref038","doi-asserted-by":"crossref","first-page":"e10177","DOI":"10.1371\/journal.pone.0010177","article-title":"High-content, image-based screening for drug targets in yeast","volume":"5","author":"S Ohnuki","year":"2010","journal-title":"PLoS One"},{"key":"pcbi.1009302.ref039","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nature11003","article-title":"The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity","volume":"483","author":"J Barretina","year":"2012","journal-title":"Nature"},{"key":"pcbi.1009302.ref040","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.cell.2016.06.017","article-title":"A Landscape of Pharmacogenomic Interactions in Cancer","volume":"166","author":"F Iorio","year":"2016","journal-title":"Cell"},{"key":"pcbi.1009302.ref041","doi-asserted-by":"crossref","first-page":"e1006878","DOI":"10.1371\/journal.pcbi.1006878","article-title":"Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network","volume":"15","author":"PMU Ung","year":"2019","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1009302.ref042","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"A Daina","year":"2017","journal-title":"Sci Rep"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1009302","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009302","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T16:10:56Z","timestamp":1633018256000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009302"}},"subtitle":[],"editor":[{"given":"Edwin","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,9,14]]},"references-count":42,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009302","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.02.15.430538","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,14]]}}}