{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:22:33Z","timestamp":1785410553653,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,29]]},"group-title":"Cancer Biology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"U.S. Department of Defense","award":["W81XWH-17-1-0242"],"award-info":[{"award-number":["W81XWH-17-1-0242"]}]},{"name":"U.S. Department of Defense","award":["W81XWH-17-1-0243"],"award-info":[{"award-number":["W81XWH-17-1-0243"]}]},{"award":["5T32-CA009531-29"],"award-info":[{"award-number":["5T32-CA009531-29"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Androgen receptor (AR)-dependent prostate cancer (PCa) cells require co-activation of ELK1 by AR to activate a critical set of cell cycle and mitosis genes, regardless of hormone - sensitivity. A small molecule antagonist (KCI807) that inhibits AR-dependent growth by selectively binding to AR and blocking its association with ELK1 is limited as a drug by auto-induced metabolism. Using structure-activity data, consistent with modeling a physically mapped KCI807 binding pocket, we developed a new class of compounds with a different core structure comprising 5-Hydroxy-2-(3-hydroxyphenyl)-1-methylquinolin-4(1H)-one (KCI830), with variable N- substituents. The compound with a N-2,2,2-trifluoroethyl substitution (KCI838) was the fastest acting and most potent inhibitor of AR-dependent cell growth and colony formation in PCa model cells, including exclusively AR splice variant-dependent and other enzalutamide-resistant cells, without affecting growth of AR-negative cell lines. Critical tests were conducted to establish that KCI838 recapitulates the previously elucidated mode of action of KCI807. KCI838 selectively inhibited ELK1-dependent vs. androgen response element (ARE)-driven promoter and gene activation by AR. KCI838 blocked AR binding to ELK1\n                  <jats:italic>in situ<\/jats:italic>\n                  tested by BRET assay. Increasing the total cellular AR by \u223c2-fold using ectopic AR expression caused the predicted change in drug dose-response profile for growth, implicating AR as the exclusive target for the activity of KCI838. KCI838\u2019s molecular scaffold conferred reduced enzyme induction in primary human hepatocytes and weakened interactions with human UGT1A1 and CYP1A2. In mice bearing an aggressive, enzalutamide-resistant patient-derived PCa tumor xenograft characteristically overexpressing prostatic acid phosphatase, daily bolus injections of a soluble 3\u2019phosphate monoester prodrug of KCI838 (KCI838PME) progressively inhibited tumor growth, concomitant with tumor accumulation of active hydrophobic drug, without significant toxicity. Additionally, ALZET osmotic pumps were used to establish proof-of-concept for reversible\n                  <jats:italic>in vivo<\/jats:italic>\n                  anti-tumor activity of KCI838PME administered in a low dose, controlled release mode. The results warrant investigation of KCI838PME in a controlled-release formulation, to treat PCa that is resistant to current AR-targeted therapies while obviating the need for testosterone suppression.\n                <\/jats:p>","DOI":"10.64898\/2026.05.26.727474","type":"posted-content","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:40:26Z","timestamp":1780108826000},"source":"Crossref","is-referenced-by-count":0,"title":["A Novel Drug Candidate that Selectively Targets the Critical Androgen Receptor-ELK1 Growth Axis in Advanced and Drug-Resistant Prostate Cancer"],"prefix":"10.64898","author":[{"given":"Claire","family":"Soave","sequence":"first","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Polin","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Ducker","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vy","family":"Ong","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seongho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Pardy","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter E.","family":"Shaw","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Khupse","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Toledo, Toledo, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manohar","family":"Ratnam","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060206250927000_2026.05.26.727474v1.1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-2815"},{"key":"2026060206250927000_2026.05.26.727474v1.2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.35.2005"},{"key":"2026060206250927000_2026.05.26.727474v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.soncn.2011.07.002"},{"key":"2026060206250927000_2026.05.26.727474v1.4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.10.1949"},{"key":"2026060206250927000_2026.05.26.727474v1.5","doi-asserted-by":"crossref","unstructured":"Rice MA , Malhotra SV , Stoyanova T . Second-Generation Antiandrogens: From Discovery to Standard of Care in Castration Resistant Prostate Cancer. Frontiers in Oncology. 2019;Volume 9 - 2019.","DOI":"10.3389\/fonc.2019.00801"},{"issue":"1","key":"2026060206250927000_2026.05.26.727474v1.6","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nrurol.2013.274","article-title":"CYP17 inhibitors--abiraterone, C17,20-lyase inhibitors and multi-targeting agents","volume":"11","year":"2014","journal-title":"Nat Rev Urol."},{"key":"2026060206250927000_2026.05.26.727474v1.7","doi-asserted-by":"publisher","DOI":"10.1210\/me.2010-0469"},{"key":"2026060206250927000_2026.05.26.727474v1.8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.352930"},{"key":"2026060206250927000_2026.05.26.727474v1.9","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.1802"},{"key":"2026060206250927000_2026.05.26.727474v1.10","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-014-0177-y"},{"key":"2026060206250927000_2026.05.26.727474v1.11","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3630"},{"key":"2026060206250927000_2026.05.26.727474v1.12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41824"},{"key":"2026060206250927000_2026.05.26.727474v1.13","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2012-3457"},{"key":"2026060206250927000_2026.05.26.727474v1.14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1308587110"},{"issue":"1","key":"2026060206250927000_2026.05.26.727474v1.15","doi-asserted-by":"crossref","first-page":"13668","DOI":"10.1038\/ncomms13668","article-title":"Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer","volume":"7","year":"2016","journal-title":"Nature Communications"},{"key":"2026060206250927000_2026.05.26.727474v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz286"},{"key":"2026060206250927000_2026.05.26.727474v1.17","first-page":"419174","article-title":"An update on the changing indications for androgen deprivation therapy for prostate cancer","volume":"2011","year":"2011","journal-title":"Prostate Cancer"},{"key":"2026060206250927000_2026.05.26.727474v1.18","doi-asserted-by":"publisher","DOI":"10.1097\/00042307-200405000-00007"},{"key":"2026060206250927000_2026.05.26.727474v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(03)00031-1"},{"key":"2026060206250927000_2026.05.26.727474v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/358414a0"},{"key":"2026060206250927000_2026.05.26.727474v1.21","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn099"},{"key":"2026060206250927000_2026.05.26.727474v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.03.018"},{"key":"2026060206250927000_2026.05.26.727474v1.23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.438473"},{"key":"2026060206250927000_2026.05.26.727474v1.24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.745596"},{"issue":"14","key":"2026060206250927000_2026.05.26.727474v1.25","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1042\/BCJ20220297","article-title":"Identification of ELK1 interacting peptide segments in the androgen receptor","volume":"479","year":"2022","journal-title":"Biochem J"},{"issue":"2","key":"2026060206250927000_2026.05.26.727474v1.26","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/pros.23932","article-title":"The ternary complex factor protein ELK1 is an independent prognosticator of disease recurrence in prostate cancer","volume":"80","year":"2020","journal-title":"Prostate"},{"key":"2026060206250927000_2026.05.26.727474v1.27","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0982"},{"key":"2026060206250927000_2026.05.26.727474v1.28","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.122.000589"},{"key":"2026060206250927000_2026.05.26.727474v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.217155"},{"key":"2026060206250927000_2026.05.26.727474v1.30","doi-asserted-by":"crossref","first-page":"102057","DOI":"10.1016\/j.ctrv.2020.102057","article-title":"Immune-checkpoint inhibitors and metastatic prostate cancer therapy: Learning by making mistakes","volume":"88","year":"2020","journal-title":"Cancer Treat Rev"},{"key":"2026060206250927000_2026.05.26.727474v1.31","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-021-01061-x"},{"key":"2026060206250927000_2026.05.26.727474v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.001"},{"key":"2026060206250927000_2026.05.26.727474v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2014.18"},{"key":"2026060206250927000_2026.05.26.727474v1.34","doi-asserted-by":"publisher","DOI":"10.4103\/1008-682X.181081"},{"issue":"3","key":"2026060206250927000_2026.05.26.727474v1.35","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1089\/adt.2021.128","article-title":"Development of a High-Throughput Screening Assay for Small-Molecule Inhibitors of Androgen Receptor Splice Variants","volume":"20","year":"2022","journal-title":"Assay Drug Dev Technol"},{"key":"2026060206250927000_2026.05.26.727474v1.36","doi-asserted-by":"crossref","first-page":"104639","DOI":"10.1016\/j.bioorg.2021.104639","article-title":"Quinolines, a perpetual, multipurpose scaffold in medicinal chemistry","volume":"109","year":"2021","journal-title":"Bioorg Chem"},{"issue":"1","key":"2026060206250927000_2026.05.26.727474v1.37","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1039\/C9MD00396G","article-title":"Scaffold-hopping as a strategy to address metabolic liabilities of aromatic compounds","volume":"11","year":"2020","journal-title":"RSC Med Chem"},{"issue":"2","key":"2026060206250927000_2026.05.26.727474v1.38","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0026-895X(25)13599-2","article-title":"Quinolone antibacterial agents: relationship between structure and in vitro inhibition of the human cytochrome P450 isoform CYP1A2","volume":"43","year":"1993","journal-title":"Mol Pharmacol"},{"key":"2026060206250927000_2026.05.26.727474v1.39","doi-asserted-by":"crossref","unstructured":"B\u00fcnning P. Drug\u2013Drug Interaction: Enzyme Induction. In: Vogel HG , Maas J , Hock FJ , Mayer D , editors. Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Berlin, Heidelberg: Springer Berlin Heidelberg; 2013. p. 975\u201387.","DOI":"10.1007\/978-3-642-25240-2_43"},{"key":"2026060206250927000_2026.05.26.727474v1.40","doi-asserted-by":"crossref","unstructured":"Dudda A , Kuerzel GU . Drug\u2013Drug Interaction: Enzyme Inhibition. In: Vogel HG , Maas J , Hock FJ , Mayer D , editors. Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Berlin, Heidelberg: Springer Berlin Heidelberg; 2013. p. 989\u20131004.","DOI":"10.1007\/978-3-642-25240-2_44"},{"issue":"4","key":"2026060206250927000_2026.05.26.727474v1.41","doi-asserted-by":"crossref","first-page":"R589","DOI":"10.1152\/ajpregu.00259.2022","article-title":"Androgen-deprivation therapy with leuprolide increases abdominal adiposity without causing cardiac dysfunction in middle-aged male mice: effect of sildenafil. American Journal of Physiology-Regulatory","volume":"324","year":"2023","journal-title":"Integrative and Comparative Physiology"},{"key":"2026060206250927000_2026.05.26.727474v1.42","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.121.262413"},{"key":"2026060206250927000_2026.05.26.727474v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2021.03.004"},{"key":"2026060206250927000_2026.05.26.727474v1.44","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021108599"},{"key":"2026060206250927000_2026.05.26.727474v1.45","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E11-09-0781"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.26.727474","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T13:25:21Z","timestamp":1780406721000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.26.727474"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":45,"URL":"https:\/\/doi.org\/10.64898\/2026.05.26.727474","relation":{},"subject":[],"published":{"date-parts":[[2026,5,29]]},"subtype":"preprint"}}