{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:55:51Z","timestamp":1785426951178,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,5]]},"group-title":"Molecular Biology","reference-count":32,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["U45DK104310"],"award-info":[{"award-number":["U45DK104310"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DK131175"],"award-info":[{"award-number":["R01DK131175"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DK127081"],"award-info":[{"award-number":["R01DK127081"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"U.S. National Science Foundation","doi-asserted-by":"crossref","award":["NSF DMR-2221086"],"award-info":[{"award-number":["NSF DMR-2221086"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02tvrwm90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Prostate cancer (PCa) is one of the principal contributors to health burden in the aging male population. PCa develops through dysregulation of androgen receptor (AR) signaling pathways. Despite improvements in diagnostic techniques and interventions, no pharmacological measures with long term efficacy have been established once PCa advances to castration resistant prostate cancer (CRPC). To circumvent this issue, tetra-aryl cyclobutanes (CBs) have been proposed as structurally distinct compounds with a mechanism of action differing from traditional androgen receptor signaling inhibitor (ARSIs). Here, we apply principles of crystal engineering and solid state synthesis to expand the class of CBs through strategic derivatization. The synthesis of the CB occurs quantitatively, producing no side products and eliminating the need for product purification. We demonstrate how head-to-tail stacking interactions of halo-pyrimidine rings can be exploited to stack and align unsymmetrical alkenes to undergo [2+2] photodimerization to generate the CB in the solid state. We examine the structure-function relationships of CBs\n                  <jats:italic>in vitro<\/jats:italic>\n                  by profiling AR mediated transcriptional activity, receptor translocation, and cell viability. Moreover, we explore and identify putative binding interactions within CB\/AR complexes and establish an adaptive ligand-binding potential using molecular docking platforms. In total, our data suggests that CBs have unexploited therapeutic potential in CRPC and that green chemistry and crystal engineering principles offer a unique route to generating these drug candidates.\n                <\/jats:p>","DOI":"10.64898\/2026.05.01.721995","type":"posted-content","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T20:55:17Z","timestamp":1778014517000},"source":"Crossref","is-referenced-by-count":0,"title":["Profiling crystal engineered ligands for targeting treatment resistant androgen receptors"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3813-8949","authenticated-orcid":false,"given":"Avan","family":"Colah","sequence":"first","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin-Madison School of Pharmacy, Madison, WI, 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6963-527X","authenticated-orcid":false,"given":"Charles","family":"Ezekiel","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e1ra","family":"Ferkov\u00e1","sequence":"additional","affiliation":[{"name":"D\u00e9partement de pharmacologie-physiologie, Facult\u00e9 de m\u00e9decine et des sciences de la sant\u00e9, Universit\u00e9 de Sherbrooke, Sherbrooke, Qu\u00e9bec J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2032-7970","authenticated-orcid":false,"given":"Pierre-Luc","family":"Boudreault","sequence":"additional","affiliation":[{"name":"D\u00e9partement de pharmacologie-physiologie, Facult\u00e9 de m\u00e9decine et des sciences de la sant\u00e9, Universit\u00e9 de Sherbrooke, Sherbrooke, Qu\u00e9bec J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0875-677X","authenticated-orcid":false,"given":"Leonard","family":"MacGillivray","sequence":"additional","affiliation":[{"name":"D\u00e9partement de chimie, Facult\u00e9 des sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Qu\u00e9bec J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9807-2090","authenticated-orcid":false,"given":"William","family":"Ricke","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026050709451588000_2026.05.01.721995v1.1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-013-9474-0"},{"key":"2026050709451588000_2026.05.01.721995v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2012.08.053"},{"key":"2026050709451588000_2026.05.01.721995v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.10495"},{"key":"2026050709451588000_2026.05.01.721995v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(05)80067-1"},{"issue":"1","key":"2026050709451588000_2026.05.01.721995v1.5","first-page":"149","article-title":"Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome","volume":"63","year":"2003","journal-title":"Cancer Res"},{"key":"2026050709451588000_2026.05.01.721995v1.6","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0142"},{"key":"2026050709451588000_2026.05.01.721995v1.7","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0226"},{"key":"2026050709451588000_2026.05.01.721995v1.8","doi-asserted-by":"crossref","unstructured":"Gim HJ , Park J , Jung ME , Houk KN . Conformational dynamics of androgen receptors bound to agonists and antagonists. 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Cyclobutanes in Small-Molecule Drug Candidates. 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