{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T21:14:00Z","timestamp":1790111640262,"version":"4.0.1"},"reference-count":62,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T00:00:00Z","timestamp":1691539200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The quinoline\u20103\u2010carboxamide, Tasquinimod (TasQ), is orally active as a maintenance therapy with an on\u2010target mechanism\u2010of\u2010action via allosteric binding to HDAC4. This prevents formation of the HDAC4\/NCoR1\/HDAC3 complex, disrupting HIF\u20101\u03b1 transcriptional activation and repressing MEF\u20102 target genes needed for adaptive survival signaling in the compromised tumor micro environment. In phase 3 clinical testing against metastatic castration\u2010resistant prostate cancer(mCRPC), TasQ (1\u2009mg\/day) increased time\u2010to\u2010progression, but not overall survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>TasQ analogs were chemically synthesized and tested for activity compared to the parental compound. These included HDAC4 enzymatic assays, qRT\u2010PCR and western blot analyses of gene and protein expression following treatment, in vitro and in vivo efficacy against multiple prostate cancer models including PDXs, pharmacokinetic analyses,AHR binding and agonist assays, SPR analyses of binding to HDAC4 and NCoR1, RNAseq analysis of in vivo tumors, 3D endothelial sprouting assays, and a targeted kinase screen. Genetic knockout or knockdown controls were used when appropriate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we document that, on this regimen (1\u2009mg\/day), TasQ blood levels are 10\u2010fold lower than the optimal concentration (\u22652\u2009\u03bcM) needed for anticancer activity, suggesting higher daily doses are needed. Unfortunately, we also demonstrate that TasQ is an arylhydrocarbon receptor (AHR) agonist, which binds with an EC50 of 1\u2009\u03bcM to produce unwanted off\u2010target side effects. Therefore, we screened a library of TasQ analogsto maximize on\u2010target versus off\u2010target activity. Using this approach, we identified ESATA\u201020, which has ~10\u2010fold lower AHR agonism and 5\u2010fold greater potency against prostate cancer patient\u2010derived xenografts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This increased therapeuticindex nominates ESATA\u201020 as a lead candidate forclinical development as an orally active third generation quinoline\u20103\u2010carboxamide analog thatretains its on\u2010target ability to disrupt HDAC4\/HIF\u20101\u03b1\/MEF\u20102\u2010dependent adaptive survival signaling in the compromisedtumor microenvironment found in mCRPC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.24606","type":"journal-article","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T05:43:46Z","timestamp":1691646226000},"page":"1470-1493","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Third generation quinoline\u20103\u2010carboxamide transcriptional disrupter of HDAC4, HIF\u20101\u03b1, and MEF\u20102 signaling for metastatic castration\u2010resistant prostate cancer"],"prefix":"10.1002","volume":"83","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3854-4658","authenticated-orcid":false,"given":"John T.","family":"Isaacs","sequence":"first","affiliation":[{"name":"Department of Oncology Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University Baltimore Maryland USA"},{"name":"Department of Pharmacology and Molecular Science Johns Hopkins University School of Medicine Baltimore Maryland USA"},{"name":"Department of Urology James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L.","family":"Dalrymple","sequence":"additional","affiliation":[{"name":"Department of Oncology Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizamma","family":"Antony","sequence":"additional","affiliation":[{"name":"Department of Oncology Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Marc Rosen","sequence":"additional","affiliation":[{"name":"Department of Oncology Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilsa M.","family":"Coleman","sequence":"additional","affiliation":[{"name":"Division of Human Biology Fred Hutchinson Cancer Research Center Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Division of Human Biology Fred Hutchinson Cancer Research Center Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Kostova","sequence":"additional","affiliation":[{"name":"Department of Oncology Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain A.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences Center for Molecular Toxicology and Carcinogenesis, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University University Park Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary H.","family":"Perdew","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences Center for Molecular Toxicology and Carcinogenesis, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University University Park Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5442-515X","authenticated-orcid":false,"given":"Samuel R.","family":"Denmeade","sequence":"additional","affiliation":[{"name":"Department of Oncology Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University Baltimore Maryland USA"},{"name":"Department of Pharmacology and Molecular Science Johns Hopkins University School of Medicine Baltimore Maryland USA"},{"name":"Department of Urology James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel S.","family":"Akinboye","sequence":"additional","affiliation":[{"name":"Department of Oncology Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9807-7433","authenticated-orcid":false,"given":"W. 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