{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T17:09:56Z","timestamp":1772125796718,"version":"3.50.1"},"reference-count":46,"publisher":"Elsevier BV","issue":"2","license":[{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T00:00:00Z","timestamp":1768003200000},"content-version":"am","delay-in-days":343,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM077430"],"award-info":[{"award-number":["GM077430"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS119873"],"award-info":[{"award-number":["NS119873"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["molpharm.aspetjournals.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Molecular Pharmacology"],"published-print":{"date-parts":[[2025,2]]},"DOI":"10.1016\/j.molpha.2024.100008","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T06:22:29Z","timestamp":1733984549000},"page":"100008","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":3,"title":["High-throughput screening identifies a novel small-molecule modulator of Hsp70 that selectively enhances ubiquitination and degradation of misfolded neuronal NO synthase"],"prefix":"10.1016","volume":"107","author":[{"given":"Anthony M.","family":"Garcia","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda K.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristian","family":"Martinez-Ramos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Morishima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miranda","family":"Lau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arya","family":"Sunil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haoming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Alt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew P.","family":"Lieberman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoichi","family":"Osawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.molpha.2024.100008_bib1","doi-asserted-by":"crossref","first-page":"7060","DOI":"10.1021\/acs.jmedchem.0c02091","article-title":"Function, therapeutic potential, and inhibition of Hsp70 chaperones","volume":"64","author":"Ambrose","year":"2021","journal-title":"J\u00a0Med Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib2","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.1128\/MCB.19.6.4535","article-title":"Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions","volume":"19","author":"Ballinger","year":"1999","journal-title":"Mol Cell Biol"},{"key":"10.1016\/j.molpha.2024.100008_bib3","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1074\/jbc.274.3.1472","article-title":"Neuronal nitric-oxide synthase is regulated by the hsp90-based chaperone system in\u00a0vivo","volume":"274","author":"Bender","year":"1999","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib4","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/351714a0","article-title":"Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase","volume":"351","author":"Bredt","year":"1991","journal-title":"Nature"},{"key":"10.1016\/j.molpha.2024.100008_bib5","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ab.2007.08.020","article-title":"High-throughput screen for small molecules that modulate the ATPase activity of the molecular chaperone DnaK","volume":"372","author":"Chang","year":"2008","journal-title":"Anal Biochem"},{"key":"10.1016\/j.molpha.2024.100008_bib6","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.chembiol.2010.12.010","article-title":"Chemical screens against a reconstituted multiprotein complex: myricetin blocks DnaJ regulation of DnaK through an allosteric mechanism","volume":"18","author":"Chang","year":"2011","journal-title":"Chem Biol"},{"key":"10.1016\/j.molpha.2024.100008_bib7","doi-asserted-by":"crossref","first-page":"33642","DOI":"10.1074\/jbc.M110.159178","article-title":"C331A mutant of neuronal nitric-oxide synthase is labilized for Hsp70\/CHIP (C terminus of HSC70-interacting protein)-dependent ubiquitination","volume":"285","author":"Clapp","year":"2010","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib8","doi-asserted-by":"crossref","first-page":"609","DOI":"10.4161\/auto.19048","article-title":"Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in\u00a0vitro and in\u00a0vivo","volume":"8","author":"Congdon","year":"2012","journal-title":"Autophagy"},{"key":"10.1016\/j.molpha.2024.100008_bib9","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1124\/mol.120.119990","article-title":"Hsp70:CHIP ubiquitinates dysfunctional but not native neuronal NO synthase","volume":"98","author":"Davis","year":"2020","journal-title":"Mol Pharmacol"},{"key":"10.1016\/j.molpha.2024.100008_bib10","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1007\/s00018-019-03302-2","article-title":"Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases","volume":"77","author":"Davis","year":"2020","journal-title":"Cell Mol Life Sci"},{"key":"10.1016\/j.molpha.2024.100008_bib11","doi-asserted-by":"crossref","first-page":"12833","DOI":"10.1074\/jbc.271.22.12833","article-title":"Reconstitution of the steroid receptor.hsp90 heterocomplex assembly system of rabbit reticulocyte lysate","volume":"271","author":"Dittmar","year":"1996","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib12","doi-asserted-by":"crossref","DOI":"10.1093\/pnasnexus\/pgad115","article-title":"Mitoribosome sensitivity to HSP70 inhibition uncovers metabolic liabilities of castration-resistant prostate cancer","volume":"2","author":"Echtenkamp","year":"2023","journal-title":"PNAS Nexus"},{"key":"10.1016\/j.molpha.2024.100008_bib13","doi-asserted-by":"crossref","first-page":"51131","DOI":"10.1074\/jbc.M404857200","article-title":"Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity","volume":"279","author":"Fewell","year":"2004","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib14","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1074\/jbc.TM118.002813","article-title":"Inhibitors and chemical probes for molecular chaperone networks","volume":"294","author":"Gestwicki","year":"2019","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib15","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3389\/fnmol.2016.00004","article-title":"The ubiquitin-proteasome system: potential therapeutic targets for Alzheimer\u2019s disease and spinal cord injury","volume":"9","author":"Gong","year":"2016","journal-title":"Front Mol Neurosci"},{"key":"10.1016\/j.molpha.2024.100008_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.neulet.2019.134678","article-title":"HSP70 and HSP90 in neurodegenerative diseases","volume":"716","author":"Gupta","year":"2020","journal-title":"Neurosci Lett"},{"key":"10.1016\/j.molpha.2024.100008_bib17","doi-asserted-by":"crossref","first-page":"3828","DOI":"10.1016\/j.bmcl.2009.04.062","article-title":"Identification of Hsp70 modulators through modeling of the substrate binding domain","volume":"19","author":"Haney","year":"2009","journal-title":"Bioorg Med Chem Lett"},{"key":"10.1016\/j.molpha.2024.100008_bib18","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1016\/j.chembiol.2014.10.016","article-title":"Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70","volume":"21","author":"Howe","year":"2014","journal-title":"Chem Biol"},{"key":"10.1016\/j.molpha.2024.100008_bib19","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41419-017-0160-y","article-title":"Sensitizing tumor cells to conventional drugs: HSP70 chaperone inhibitors, their selection and application in cancer models","volume":"9","author":"Lazarev","year":"2018","journal-title":"Cell Death Dis"},{"key":"10.1016\/j.molpha.2024.100008_bib20","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1158\/1535-7163.MCT-14-0650","article-title":"Validation of the Hsp70\u2013Bag3 protein\u2013protein interaction as a potential therapeutic target in cancer","volume":"14","author":"Li","year":"2015","journal-title":"Mol Cancer Ther"},{"key":"10.1016\/j.molpha.2024.100008_bib21","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3892\/or.2022.8443","article-title":"HSP90 inhibitors and cancer: prospects for use in targeted therapies (review)","volume":"49","author":"Li","year":"2023","journal-title":"Oncol Rep"},{"key":"10.1016\/j.molpha.2024.100008_bib22","doi-asserted-by":"crossref","first-page":"34799","DOI":"10.1074\/jbc.273.52.34799","article-title":"The C331A mutant of neuronal nitric-oxide synthase is defective in arginine binding","volume":"273","author":"Mart\u00e1sek","year":"1998","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib23","doi-asserted-by":"crossref","first-page":"5246","DOI":"10.1158\/1078-0432.CCR-19-3102","article-title":"Low-dose Hsp90 inhibitor selectively radiosensitizes HNSCC and pancreatic xenografts","volume":"26","author":"Mehta","year":"2020","journal-title":"Clin Cancer Res"},{"key":"10.1016\/j.molpha.2024.100008_bib24","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1177\/1087057110380571","article-title":"High-throughput screen for Escherichia coli heat shock protein 70 (Hsp70\/DnaK): ATPase assay in low volume by exploiting energy transfer","volume":"15","author":"Miyata","year":"2010","journal-title":"J\u00a0Biomol Screen"},{"key":"10.1016\/j.molpha.2024.100008_bib25","doi-asserted-by":"crossref","DOI":"10.1016\/j.jbc.2022.102856","article-title":"Dynamic cycling with a unique Hsp90\/Hsp70-dependent chaperone machinery and GAPDH is needed for heme insertion and activation of neuronal NO synthase","volume":"299","author":"Morishima","year":"2023","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ab.2016.07.031","article-title":"Improved method for assembly of hemeprotein neuronal NO-synthase heterodimers","volume":"511","author":"Morishima","year":"2016","journal-title":"Anal Biochem"},{"key":"10.1016\/j.molpha.2024.100008_bib27","doi-asserted-by":"crossref","first-page":"13107","DOI":"10.1016\/S0021-9258(17)36805-9","article-title":"hsp70-protein complexes. Complex stability and conformation of bound substrate protein","volume":"269","author":"Palleros","year":"1994","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib28","doi-asserted-by":"crossref","first-page":"52970","DOI":"10.1074\/jbc.M406926200","article-title":"Ubiquitylation of neuronal nitric-oxide synthase by CHIP, a chaperone-dependent E3 ligase","volume":"279","author":"Peng","year":"2004","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib29","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1146\/annurev-pharmtox-010814-124332","article-title":"Targeting Hsp90\/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases","volume":"55","author":"Pratt","year":"2015","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"10.1016\/j.molpha.2024.100008_bib30","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.chembiol.2013.10.008","article-title":"Identification of an allosteric pocket on human Hsp70 reveals a mode of inhibition of this therapeutically important protein","volume":"20","author":"Rodina","year":"2013","journal-title":"Chem Biol"},{"key":"10.1016\/j.molpha.2024.100008_bib31","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.jmb.2011.06.003","article-title":"Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones","volume":"411","author":"Rousaki","year":"2011","journal-title":"J\u00a0Mol Biol"},{"key":"10.1016\/j.molpha.2024.100008_bib32","doi-asserted-by":"crossref","DOI":"10.1016\/j.bmcl.2021.128025","article-title":"Inhibitors of heat shock protein 70 (Hsp70) with enhanced metabolic stability reduce Tau levels","volume":"41","author":"Shao","year":"2021","journal-title":"Bioorg Med Chem Lett"},{"key":"10.1016\/j.molpha.2024.100008_bib33","doi-asserted-by":"crossref","first-page":"6163","DOI":"10.1021\/acs.jmedchem.8b00583","article-title":"Exploration of benzothiazole rhodacyanines as allosteric inhibitors of protein\u2013protein interactions with heat shock protein 70 (Hsp70)","volume":"61","author":"Shao","year":"2018","journal-title":"J\u00a0Med Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib34","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1111\/cbdd.13486","article-title":"Spotlight on 17-AAG as an Hsp90 inhibitor for molecular targeted cancer treatment","volume":"93","author":"Talaei","year":"2019","journal-title":"Chem Biol Drug Des"},{"key":"10.1016\/j.molpha.2024.100008_bib35","doi-asserted-by":"crossref","first-page":"4014","DOI":"10.1074\/jbc.RA117.001575","article-title":"High-throughput screen for inhibitors of protein\u2013protein interactions in a reconstituted heat shock protein 70 (Hsp70) complex","volume":"293","author":"Taylor","year":"2018","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib36","doi-asserted-by":"crossref","DOI":"10.3389\/fnmol.2023.1230436","article-title":"Closest horizons of Hsp70 engagement to manage neurodegeneration","volume":"16","author":"Venediktov","year":"2023","journal-title":"Front Mol Neurosci"},{"key":"10.1016\/j.molpha.2024.100008_bib37","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nchembio.1140","article-title":"Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation","volume":"9","author":"Wang","year":"2013","journal-title":"Nat Chem Biol"},{"key":"10.1016\/j.molpha.2024.100008_bib38","doi-asserted-by":"crossref","first-page":"15714","DOI":"10.1074\/jbc.M109.098806","article-title":"Inhibition of Hsp70 by methylene blue affects signaling protein function and ubiquitination and modulates polyglutamine protein degradation","volume":"285","author":"Wang","year":"2010","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib39","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1021\/jm801627a","article-title":"Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design","volume":"52","author":"Williamson","year":"2009","journal-title":"J\u00a0Med Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib40","doi-asserted-by":"crossref","DOI":"10.1002\/pro.5022","article-title":"DSFworld: a flexible and precise tool to analyze differential scanning fluorimetry data","volume":"33","author":"Wu","year":"2024","journal-title":"Protein Sci"},{"key":"10.1016\/j.molpha.2024.100008_bib41","doi-asserted-by":"crossref","DOI":"10.1016\/j.xpro.2023.102688","article-title":"Protocol for performing and optimizing differential scanning fluorimetry experiments","volume":"4","author":"Wu","year":"2023","journal-title":"STAR Protoc"},{"key":"10.1016\/j.molpha.2024.100008_bib42","doi-asserted-by":"crossref","first-page":"19871","DOI":"10.1074\/jbc.M100034200","article-title":"A\u00a0HECT domain E3 enzyme assembles novel polyubiquitin chains","volume":"276","author":"You","year":"2001","journal-title":"J\u00a0Biol Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib43","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.chembiol.2016.04.014","article-title":"Stabilizing the Hsp70-Tau complex promotes turnover in models of tauopathy","volume":"23","author":"Young","year":"2016","journal-title":"Cell Chem Biol"},{"key":"10.1016\/j.molpha.2024.100008_bib44","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ejmech.2015.04.043","article-title":"Design and synthesis of piperidine derivatives as novel human heat shock protein 70 inhibitors for the treatment of drug-resistant tumors","volume":"97","author":"Zeng","year":"2015","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.molpha.2024.100008_bib45","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1177\/108705719900400206","article-title":"A\u00a0simple statistical parameter for use in evaluation and validation of high throughput screening assays","volume":"4","author":"Zhang","year":"1999","journal-title":"J\u00a0Biomol Screen"},{"key":"10.1016\/j.molpha.2024.100008_bib46","first-page":"431","article-title":"Heme deficiency interferes with the Ras-mitogen-activated protein kinase signaling pathway and expression of a subset of neuronal genes1","volume":"13","author":"Zhu","year":"2002","journal-title":"Cell Growth Differ"}],"container-title":["Molecular Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0026895X24230145?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0026895X24230145?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T23:05:05Z","timestamp":1740697505000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0026895X24230145"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":46,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["S0026895X24230145"],"URL":"https:\/\/doi.org\/10.1016\/j.molpha.2024.100008","relation":{},"ISSN":["0026-895X"],"issn-type":[{"value":"0026-895X","type":"print"}],"subject":[],"published":{"date-parts":[[2025,2]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"High-throughput screening identifies a novel small-molecule modulator of Hsp70 that selectively enhances ubiquitination and degradation of misfolded neuronal NO synthase","name":"articletitle","label":"Article Title"},{"value":"Molecular Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.molpha.2024.100008","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2024 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"100008"}}