{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T15:37:59Z","timestamp":1791128279884,"version":"4.1.0"},"reference-count":58,"publisher":"American Chemical Society (ACS)","issue":"16","license":[{"start":{"date-parts":[[2015,4,24]],"date-time":"2015-04-24T00:00:00Z","timestamp":1429833600000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,8,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Creutzfeldt\u2013Jakob disease (CJD) is a rare but invariably fatal neurodegenerative disease caused by misfolding of an endogenous protein into an alternative pathogenic conformation. The details of protein misfolding and aggregation are not well understood nor are the mechanism(s) by which the aggregated protein confers cellular toxicity. While there is as yet no clear consensus about how best to intervene therapeutically in CJD, prion infections can be propagated in cell culture and in experimental animals, affording both in vitro and in vivo models of disease. Here we review recent lead discovery efforts for CJD, with a focus on our own efforts to optimize 2-aminothiazole analogues for anti-prion potency in cells and for brain exposure in mice. The compounds that emerged from this effort were found to be efficacious in multiple animal models of prion disease even as they revealed new challenges for the field, including the emergence of resistant prion strains.<\/jats:p>","DOI":"10.1021\/jm5001425","type":"journal-article","created":{"date-parts":[[2014,4,24]],"date-time":"2014-04-24T09:38:22Z","timestamp":1398332302000},"page":"6919-6929","source":"Crossref","is-referenced-by-count":24,"title":["Successes and Challenges in\nPhenotype-Based Lead Discovery\nfor Prion Diseases"],"prefix":"10.1021","volume":"57","author":[{"given":"Sina","family":"Ghaemmaghami","sequence":"first","affiliation":[{"name":"University of Rochester , , 326 Hutchison Hall , , ,","place":["Rochester, New York, United States, 14627"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda","family":"Russo","sequence":"additional","affiliation":[{"name":"University of Rochester , , 326 Hutchison Hall , , ,","place":["Rochester, New York, United States, 14627"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam R.","family":"Renslo","sequence":"additional","affiliation":[{"name":"University of California, San Francisco , , Byers Hall 503D, 1700 4th Street , , ,","place":["San Francisco, California, United States, 94158"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,4,24]]},"reference":[{"key":"2026090218164647500_cit1","doi-asserted-by":"crossref","first-page":"a006833","DOI":"10.1101\/cshperspect.a006833","article-title":"Prions","volume":"3","author":"Colby","year":"2011","journal-title":"Cold Spring Harbor Perspect\nBiol."},{"key":"2026090218164647500_cit2","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1126\/science.6801762","article-title":"Novel proteinaceous\ninfectious particles cause scrapie","volume":"216","author":"Prusiner","year":"1982","journal-title":"Science"},{"key":"2026090218164647500_cit3","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1056\/NEJM200105173442006","article-title":"Shattuck\nlecture\u2500neurodegenerative diseases and prions","volume":"344","author":"Prusiner","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"2026090218164647500_cit4","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1002\/ana.410200507","article-title":"Creutzfeldt\u2013Jakob\ndisease: clinical analysis of a consecutive series of 230 neuropathologically\nverified cases","volume":"20","author":"Brown","year":"1986","journal-title":"Ann. Neurol."},{"key":"2026090218164647500_cit5","first-page":"1","article-title":"The clinical\ncharacteristics of transmissible Creutzfeldt\u2013Jakob disease","volume":"96","author":"Roos","year":"1973","journal-title":"Brain"},{"key":"2026090218164647500_cit6","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1146\/annurev.neuro.24.1.519","article-title":"Prion diseases\nof humans and animals: their causes and molecular basis","volume":"24","author":"Collinge","year":"2001","journal-title":"Annu. Rev. Neurosci."},{"key":"2026090218164647500_cit7","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1038\/nrmicro1025","article-title":"The state\nof the prion","volume":"2","author":"Weissmann","year":"2004","journal-title":"Nat. Rev. Microbiol."},{"key":"2026090218164647500_cit8","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1073\/pnas.97.1.145","article-title":"NMR solution\nstructure of the human prion protein","volume":"97","author":"Zahn","year":"2000","journal-title":"Proc.\nNatl. Acad. Sci. U.S.A."},{"key":"2026090218164647500_cit9","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/nature12402","article-title":"The toxicity\nof antiprion antibodies is mediated by the flexible tail of the prion\nprotein","volume":"501","author":"Sonati","year":"2013","journal-title":"Nature"},{"key":"2026090218164647500_cit10","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.str.2013.11.009","article-title":"Structural basis of prion inhibition\nby phenothiazine compounds","volume":"22","author":"Baral","year":"2014","journal-title":"Structure"},{"key":"2026090218164647500_cit11","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1126\/science.1151839","article-title":"Amyloid fibrils\nof the het-s(218-289) prion form a\nbeta solenoid with a triangular hydrophobic core","volume":"319","author":"Wasmer","year":"2008","journal-title":"Science"},{"key":"2026090218164647500_cit12","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/356577a0","article-title":"Normal development and behaviour\nof mice lacking the\nneuronal cell-surface prp protein","volume":"356","author":"Bueler","year":"1992","journal-title":"Nature"},{"key":"2026090218164647500_cit13","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/nbt1271","article-title":"Production of cattle lacking prion\nprotein","volume":"25","author":"Richt","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"2026090218164647500_cit14","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/mrd.20960","article-title":"Generation of goats\nlacking prion protein","volume":"76","author":"Yu","year":"2009","journal-title":"Mol. Reprod. Dev."},{"key":"2026090218164647500_cit15","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/nn.3120","article-title":"Prion propagation, toxicity and degradation","volume":"15","author":"Aguzzi","year":"2012","journal-title":"Nat. Neurosci."},{"key":"2026090218164647500_cit16","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/j.1423-0410.2006.00833.x","article-title":"Creutzfeldt\u2013Jakob\ndisease and blood transfusion: results of the UK transfusion medicine\nepidemiological review study","volume":"91","author":"Hewitt","year":"2006","journal-title":"Vox Sang."},{"key":"2026090218164647500_cit17","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1212\/01.WNL.0000113764.35026.EF","article-title":"Efficacy of flupirtine on cognitive\nfunction in patients with CJD: a double-blind study","volume":"62","author":"Otto","year":"2004","journal-title":"Neurology"},{"key":"2026090218164647500_cit18","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1212\/WNL.0b013e3182a9f3b4","article-title":"Quinacrine treatment\ntrial for sporadic Creutzfeldt\u2013Jakob disease","volume":"81","author":"Geschwind","year":"2013","journal-title":"Neurology"},{"key":"2026090218164647500_cit19","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/S1474-4422(13)70307-7","article-title":"Doxycycline in Creutzfeldt\u2013Jakob\ndisease: a phase 2, randomised, double-blind, placebo-controlled trial","volume":"13","author":"Haik","year":"2014","journal-title":"Lancet Neurol."},{"key":"2026090218164647500_cit20","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1002\/cmdc.201100119","article-title":"From high-throughput\ncell culture screening to mouse model: identification of new inhibitor\nclasses against prion disease","volume":"6","author":"Geissen","year":"2011","journal-title":"ChemMedChem"},{"key":"2026090218164647500_cit21","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1051\/vetres:2007049","article-title":"Cell models\nof prion infection","volume":"39","author":"Vilette","year":"2008","journal-title":"Vet. Res."},{"key":"2026090218164647500_cit22","doi-asserted-by":"crossref","first-page":"3501","DOI":"10.1073\/pnas.0409651102","article-title":"Diagnosis of human prion disease","volume":"102","author":"Safar","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090218164647500_cit23","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1111\/j.1469-445X.2000.02091.x","article-title":"Neuroinvasion of prions: insights\nfrom mouse models","volume":"85","author":"Brandner","year":"2000","journal-title":"Exp. Physiol."},{"key":"2026090218164647500_cit24","doi-asserted-by":"crossref","first-page":"15002","DOI":"10.1073\/pnas.0907339106","article-title":"Measuring prions\nby bioluminescence imaging","volume":"106","author":"Tamguney","year":"2009","journal-title":"Proc. Natl. Acad.\nSci. U.S.A."},{"key":"2026090218164647500_cit25","doi-asserted-by":"crossref","first-page":"11921","DOI":"10.1073\/pnas.0702671104","article-title":"Hot spots in prion\nprotein for pathogenic conversion","volume":"104","author":"Kuwata","year":"2007","journal-title":"Proc. Natl.\nAcad. Sci. U.S.A."},{"key":"2026090218164647500_cit26","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1093\/brain\/awl150","article-title":"A systematic review of prion therapeutics in experimental\nmodels","volume":"129","author":"Trevitt","year":"2006","journal-title":"Brain"},{"key":"2026090218164647500_cit27","first-page":"144","article-title":"Prion disease:\nchemotherapeutic strategies","volume":"12","author":"Sim","year":"2012","journal-title":"Infect. Disord.:\nDrug Targets"},{"key":"2026090218164647500_cit28","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/pro.2180","article-title":"Characterizing antiprion\ncompounds based on their binding\nproperties to prion proteins: implications as medical chaperones","volume":"22","author":"Kamatari","year":"2013","journal-title":"Protein Sci."},{"key":"2026090218164647500_cit29","doi-asserted-by":"crossref","first-page":"e1000673","DOI":"10.1371\/journal.ppat.1000673","article-title":"Continuous quinacrine treatment results in the formation\nof drug-resistant prions","volume":"5","author":"Ghaemmaghami","year":"2009","journal-title":"PLoS Pathog."},{"key":"2026090218164647500_cit30","doi-asserted-by":"crossref","first-page":"10849","DOI":"10.1073\/pnas.162195499","article-title":"Tetracyclines affect prion infectivity","volume":"99","author":"Forloni","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090218164647500_cit31","first-page":"15","article-title":"Amyloidophilic compounds for prion diseases","volume":"9","author":"Teruya","year":"2009","journal-title":"Infect. Disord.: Drug Targets"},{"key":"2026090218164647500_cit32","doi-asserted-by":"crossref","first-page":"206ra138","DOI":"10.1126\/scitranslmed.3006767","article-title":"Oral treatment targeting the unfolded\nprotein response prevents neurodegeneration and clinical disease in\nprion-infected mice","volume":"5","author":"Moreno","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"2026090218164647500_cit33","doi-asserted-by":"crossref","first-page":"7193","DOI":"10.1021\/jm300713s","article-title":"Discovery\nof 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class\ninhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase\n(PERK)","volume":"55","author":"Axten","year":"2012","journal-title":"J. Med. Chem."},{"key":"2026090218164647500_cit34","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s00401-013-1114-9","article-title":"Anle138b: a novel oligomer modulator\nfor disease-modifying therapy of neurodegenerative diseases such as\nprion and Parkinson\u2019s disease","volume":"125","author":"Wagner","year":"2013","journal-title":"Acta Neuropathol."},{"key":"2026090218164647500_cit35","doi-asserted-by":"crossref","first-page":"E4160","DOI":"10.1073\/pnas.1317164110","article-title":"Drug resistance\nconfounding prion therapeutics","volume":"110","author":"Berry","year":"2013","journal-title":"Proc. Natl.\nAcad. Sci. U.S.A."},{"key":"2026090218164647500_cit36","doi-asserted-by":"crossref","first-page":"10288","DOI":"10.1128\/JVI.77.19.10288-10294.2003","article-title":"New inhibitors of scrapie-associated prion protein\nformation in a library of 2000 drugs and natural products","volume":"77","author":"Kocisko","year":"2003","journal-title":"J. Virol."},{"key":"2026090218164647500_cit37","doi-asserted-by":"crossref","first-page":"7785","DOI":"10.1128\/JVI.79.12.7785-7791.2005","article-title":"Systematic identification of antiprion drugs by high-throughput screening\nbased on scanning for intensely fluorescent targets","volume":"79","author":"Bertsch","year":"2005","journal-title":"J. Virol."},{"key":"2026090218164647500_cit38","doi-asserted-by":"crossref","first-page":"3408","DOI":"10.1128\/JVI.02145-09","article-title":"Discovery of 2-aminothiazoles\nas potent antiprion compounds","volume":"84","author":"Ghaemmaghami","year":"2010","journal-title":"J. Virol."},{"key":"2026090218164647500_cit39","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1021\/tx700270r","article-title":"A rational\nchemical\nintervention strategy to circumvent bioactivation liabilities associated\nwith a nonpeptidyl thrombopoietin receptor agonist containing a 2-amino-4-arylthiazole\nmotif","volume":"20","author":"Kalgutkar","year":"2007","journal-title":"Chem. Res. Toxicol."},{"key":"2026090218164647500_cit40","doi-asserted-by":"crossref","first-page":"3766","DOI":"10.1021\/jm060347y","article-title":"Discovery and evaluation of N-cyclopropyl-2,4-difluoro-5-((2-(pyridin-2-ylamino)thiazol-5-ylmethyl)amino)benzamide\n(BMS-605541), a selective and orally efficacious inhibitor of vascular\nendothelial growth factor receptor-2","volume":"49","author":"Borzilleri","year":"2006","journal-title":"J. Med.\nChem."},{"key":"2026090218164647500_cit41","doi-asserted-by":"crossref","first-page":"6819","DOI":"10.1021\/jm060727j","article-title":"2-Aminothiazole\nas a novel kinase inhibitor template. Structure\u2013activity relationship\nstudies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide\n(dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor","volume":"49","author":"Das","year":"2006","journal-title":"J. Med. Chem."},{"key":"2026090218164647500_cit42","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1016\/j.bmcl.2005.04.021","article-title":"A new orally bioavailable dual adenosine a2b\/a3 receptor\nantagonist with therapeutic potential","volume":"15","author":"Press","year":"2005","journal-title":"Bioorg.\nMed. Chem. Lett."},{"key":"2026090218164647500_cit43","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1021\/jm0003945","article-title":"Thiazole\nand thiadiazole analogues as a novel class of adenosine receptor antagonists","volume":"44","author":"van Muijlwijk-Koezen","year":"2001","journal-title":"J. Med. Chem."},{"key":"2026090218164647500_cit44","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.ccr.2008.06.004","article-title":"A molecule targeting VHL-deficient renal cell carcinoma\nthat induces autophagy","volume":"14","author":"Turcotte","year":"2008","journal-title":"Cancer Cell"},{"key":"2026090218164647500_cit45","doi-asserted-by":"crossref","first-page":"6554","DOI":"10.1016\/j.bmcl.2011.08.060","article-title":"Aminothiazoles\nas gamma-secretase\nmodulators","volume":"21","author":"Lubbers","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026090218164647500_cit46","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.neuron.2010.08.018","article-title":"Modulation\nof gamma-secretase reduces beta-amyloid deposition in a transgenic\nmouse model of Alzheimer\u2019s disease","volume":"67","author":"Kounnas","year":"2010","journal-title":"Neuron"},{"key":"2026090218164647500_cit47","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1021\/jm101250y","article-title":"2-Aminothiazoles\nas therapeutic leads for prion diseases","volume":"54","author":"Gallardo-Godoy","year":"2011","journal-title":"J.\nMed. Chem."},{"key":"2026090218164647500_cit48","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/cmdc.201300007","article-title":"2-Aminothiazoles\nwith improved pharmacotherapeutic properties for treatment of prion\ndisease","volume":"8","author":"Li","year":"2013","journal-title":"ChemMedChem"},{"key":"2026090218164647500_cit49","doi-asserted-by":"crossref","first-page":"10415","DOI":"10.1074\/jbc.M109.045112","article-title":"Chemical induction of misfolded prion protein conformers\nin cell culture","volume":"285","author":"Ghaemmaghami","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026090218164647500_cit50","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1007\/s11095-012-0912-4","article-title":"Pharmacokinetics\nand metabolism of 2-aminothiazoles with antiprion activity in mice","volume":"30","author":"Silber","year":"2013","journal-title":"Pharm. Res."},{"key":"2026090218164647500_cit51","doi-asserted-by":"crossref","first-page":"7559","DOI":"10.1021\/jm060642i","article-title":"Structure\u2013brain exposure relationships","volume":"49","author":"Hitchcock","year":"2006","journal-title":"J. Med. Chem."},{"key":"2026090218164647500_cit52","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1124\/jpet.113.205799","article-title":"Biaryl\namides and hydrazones as therapeutics\nfor prion disease in transgenic mice","volume":"347","author":"Lu","year":"2013","journal-title":"J. Pharmacol.\nExp. Ther."},{"key":"2026090218164647500_cit53","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1126\/science.1183218","article-title":"Darwinian evolution of prions in\ncell culture","volume":"327","author":"Li","year":"2010","journal-title":"Science"},{"key":"2026090218164647500_cit54","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.2174\/15680266113136660168","article-title":"Strain specificity and drug resistance\nin anti-prion\ntherapy","volume":"13","author":"Miller-Vedam","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"2026090218164647500_cit55","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1126\/science.1222951","article-title":"Cell biology.\nA unifying role for prions in neurodegenerative diseases","volume":"336","author":"Prusiner","year":"2012","journal-title":"Science"},{"key":"2026090218164647500_cit56","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature12481","article-title":"Self-propagation of pathogenic protein aggregates in\nneurodegenerative diseases","volume":"501","author":"Jucker","year":"2013","journal-title":"Nature"},{"key":"2026090218164647500_cit57","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.cell.2013.05.057","article-title":"Distinct alpha-synuclein\nstrains\ndifferentially promote tau inclusions in neurons","volume":"154","author":"Guo","year":"2013","journal-title":"Cell"},{"key":"2026090218164647500_cit58","doi-asserted-by":"crossref","first-page":"9535","DOI":"10.1073\/pnas.1301175110","article-title":"Brain homogenates\nfrom human tauopathies induce tau inclusions in mouse brain","volume":"110","author":"Clavaguera","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."}],"container-title":["Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jm5001425","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/16\/6919\/12872100\/jm5001425.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/16\/6919\/12872100\/jm5001425.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T22:17:19Z","timestamp":1788387439000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article\/57\/16\/6919\/1300337\/Successes-and-Challenges-in-Phenotype-Based-Lead"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,24]]},"references-count":58,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2014,4,24]]},"published-print":{"date-parts":[[2014,8,28]]}},"URL":"https:\/\/doi.org\/10.1021\/jm5001425","relation":{},"ISSN":["0022-2623","1520-4804"],"issn-type":[{"value":"0022-2623","type":"print"},{"value":"1520-4804","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,24]]}}}