{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T07:58:14Z","timestamp":1790582294147,"version":"4.1.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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 pathway inhibitor (ARPI).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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. 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 in vitro by profiling AR mediated transcriptional activity, receptor translocation, and cell viability. Moreover, we explored putative binding interactions of ClCB and BrCB ligands across distinct AR mutants (wild-type, T877A, and F877L\/T878A) using molecular docking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results\/Discussion<\/jats:title>\n                    <jats:p>In total, our data suggest that CBs have unexploited therapeutic potential in CRPC and that green chemistry and crystal engineering principles offer a unique route to generate these drug candidates.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1813002","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T07:44:54Z","timestamp":1790581494000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Profiling crystal engineered ligands for targeting treatment resistant androgen receptors"],"prefix":"10.3389","volume":"17","author":[{"given":"Avan Navaz","family":"Colah","sequence":"first","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin-Madison School of Pharmacy","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles Izuchukwu","family":"Ezekiel","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Iowa","place":["Iowa, IA, United States"]}],"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","place":["Sherbrooke, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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","place":["Sherbrooke, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard R","family":"MacGillivray","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Chimie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke","place":["Sherbrooke, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A","family":"Ricke","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Wisconsin School of Medicine and Public Health","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1158\/0008-5472.CAN-22-1065","article-title":"Establishment of the LNCaP cell line \u2013 the dawn of an era for prostate cancer research","volume":"82","author":"Abate-Shen","year":"2022","journal-title":"Cancer Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1016\/j.eururo.2012.08.053","article-title":"Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity","volume":"63","author":"Beltran","year":"2013","journal-title":"Eur. Urol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"11514","DOI":"10.1021\/acs.chemrev.1c00987","article-title":"Crystal engineering of pharmaceutical cocrystals in the discovery and development of improved drugs","volume":"122","author":"Bolla","year":"2022","journal-title":"Chem. Rev."},{"key":"B4","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.eururo.2017.08.012","article-title":"Moving towards precision urologic oncology: targeting Enzalutamide-resistant prostate cancer and mutated forms of the androgen receptor using the novel inhibitor darolutamide (ODM-201)","volume":"73","author":"Borgmann","year":"2018","journal-title":"Eur. Urol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"8257","DOI":"10.1021\/cr500127b","article-title":"Four-membered ring-containing spirocycles: synthetic strategies and opportunities","volume":"114","author":"Carreira","year":"2014","journal-title":"Chem. Rev."},{"key":"B6","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1016\/S1470-2045(09)70229-3","article-title":"Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target","volume":"10","author":"Chen","year":"2009","journal-title":"Lancet Oncol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.3390\/cancers18061043","article-title":"Androgen receptor point mutations: a mechanism of therapeutic resistance and a framework for rational drug design","volume":"18","author":"Colah","year":"2026","journal-title":"Cancers (Basel)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"40690","DOI":"10.18632\/oncotarget.9816","article-title":"Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor","volume":"7","author":"Coleman","year":"2016","journal-title":"Oncotarget"},{"key":"B9","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1016\/j.juro.2018.04.083","article-title":"Androgen receptor targeted treatments of prostate cancer: 35 years of progress with antiandrogens","volume":"200","author":"Crawford","year":"2018","journal-title":"J. Urol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1007\/s10555-013-9474-0","article-title":"Androgen receptor signaling in prostate cancer","volume":"33","author":"Culig","year":"2014","journal-title":"Cancer Metastasis Rev."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2094","DOI":"10.1021\/acsnano.8b00932","article-title":"Multifunctional efficiency: extending the concept of atom economy to functional nanomaterials","volume":"12","author":"Freund","year":"2018","journal-title":"ACS Nano"},{"key":"B12","doi-asserted-by":"publisher","first-page":"15887","DOI":"10.1038\/s41598-021-94707-2","article-title":"Conformational dynamics of androgen receptors bound to agonists and antagonists","volume":"11","author":"Gim","year":"2021","journal-title":"Sci. Rep."},{"key":"B13","first-page":"149","article-title":"Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome","volume":"63","author":"Hara","year":"2003","journal-title":"Cancer Res."},{"key":"B14","first-page":"115","article-title":"The LNCaP cell line--a new model for studies on human prostatic carcinoma","volume":"37","author":"Horoszewicz","year":"1980","journal-title":"Prog. Clin. Biol. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1056\/NEJMc1810065","article-title":"Enzalutamide in castration-resistant prostate cancer","volume":"379","author":"Hussain","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1158\/2159-8290.CD-13-0226","article-title":"A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509","volume":"3","author":"Joseph","year":"2013","journal-title":"Cancer Discov."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1158\/2159-8290.CD-13-0142","article-title":"An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide)","volume":"3","author":"Korpal","year":"2013","journal-title":"Cancer Discov."},{"key":"B18","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1634\/theoncologist.2019-0115","article-title":"Comprehensive analysis of AR alterations in circulating tumor DNA from patients with advanced prostate cancer","volume":"25","author":"Ledet","year":"2020","journal-title":"Oncol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1021\/cr010013a","article-title":"Enantiomerically pure cyclobutane derivatives and their use in organic synthesis","volume":"103","author":"Lee-Ruff","year":"2003","journal-title":"Chem. Rev."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3347","DOI":"10.1039\/c5mb00499c","article-title":"Interaction mechanism exploration of R-bicalutamide\/S-1 with WT\/W741L AR using molecular dynamics simulations","volume":"11","author":"Liu","year":"2015","journal-title":"Mol. Biosyst."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1007\/s10822-016-9992-2","article-title":"Molecular mechanism of R-bicalutamide switching from androgen receptor antagonist to agonist induced by amino acid mutations using molecular dynamics simulations and free energy calculation","volume":"30","author":"Liu","year":"2016","journal-title":"J. Computer-Aided Mol. Des."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2792","DOI":"10.1002\/jcb.25928","article-title":"Molecular dynamics studies on the enzalutamide resistance mechanisms induced by androgen receptor mutations","volume":"118","author":"Liu","year":"","journal-title":"J. Cell. Biochem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.3390\/ijms18091823","article-title":"A molecular modeling study of the hydroxyflutamide resistance mechanism induced by androgen receptor mutations","volume":"18","author":"Liu","year":"","journal-title":"Int. J. Mol. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"4100","DOI":"10.1002\/anie.201811313","article-title":"Crystal engineering: an outlook for the future","volume":"58","author":"Nangia","year":"2019","journal-title":"Angew. Chem. Int. Ed."},{"key":"B25","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1038\/nchembio.2131","article-title":"Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer","volume":"12","author":"Pollock","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"7125","DOI":"10.1021\/jo010573+","article-title":"Arylation of halogenated pyrimidines via a Suzuki coupling reaction","volume":"66","author":"Schomaker","year":"2001","journal-title":"J. Org. Chem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/s42004-021-00493-3","article-title":"Supramolecular construction of a cyclobutane ring system with four different substituents in the solid state","volume":"4","author":"Sinnwell","year":"2021","journal-title":"Commun. Chem."},{"key":"B28","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1002\/ijc.10495","article-title":"Broadened ligand responsiveness of androgen receptor mutants obtained by random amino acid substitution of H874 and mutation hot spot T877 in prostate cancer","volume":"100","author":"Steketee","year":"2002","journal-title":"Int. J. Cancer"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3773","DOI":"10.1081\/scc-200032495","article-title":"2004. - the facile route to stereodefined alkenylsubstituted pyrimidines","volume":"34","author":"Tan","year":"2004","journal-title":"Synth. Commun."},{"key":"B30","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1126\/science.1168175","article-title":"Development of a second-generation antiandrogen for treatment of advanced prostate cancer","volume":"324","author":"Tran","year":"2009","journal-title":"Science"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e202200020","DOI":"10.1002\/cmdc.202200020","article-title":"Cyclobutanes in small\u2010molecule drug candidates","volume":"17","author":"Van Der Kolk","year":"2022","journal-title":"ChemMedChem"},{"key":"B32","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/s0006-291x(05)80067-1","article-title":"A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens","volume":"173","author":"Veldscholte","year":"1990","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B33","doi-asserted-by":"publisher","first-page":"11918","DOI":"10.1002\/anie.201502815","article-title":"Cyclobutane and cyclobutene synthesis: catalytic enantioselective [2+2] cycloadditions","volume":"54","author":"Xu","year":"2015","journal-title":"Angew. Chem. Int. Ed."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1813002\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T07:44:55Z","timestamp":1790581495000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1813002\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":33,"alternative-id":["10.3389\/fphar.2026.1813002"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1813002","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]},"article-number":"1813002"}}