{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:37:11Z","timestamp":1790617031634,"version":"4.1.0"},"reference-count":91,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Point mutations to the androgen receptor (AR) ligand-binding domain (LBD) are becoming increasingly recognized as a mechanism of therapeutic resistance in castration resistant prostate cancer (CRPC). The present review explores how point mutations induce molecular changes that contribute to the eventual treatment failure of androgen receptor pathway inhibitors (ARPIs) in CRPC. Methods: The PubMed database was searched for structural studies on the AR LBD. Eligible articles included molecular docking analysis and emphasized changes in ligand\u2013receptor interactions after point mutation. Structural data were obtained from the Protein Data Bank (PDB) using the search parameters \u201cAndrogen receptor ligand binding domain\u201d, \u201cHomo sapiens\u201d, and \u201cX-ray diffraction\u201d. PDB files of wild-type and point mutant AR LBDs were accumulated for analysis. Results: A functional shift from inhibiting to activating AR has been documented for multiple ARPIs. Crystallography data and in silico evaluation have deciphered how changes in steric hindrance of the AF-2 domain contribute to ARPI loss of function. To combat therapeutic resistance, discovery efforts have begun to consider combination approaches of orthosteric and allosteric inhibitors, as well as compounds that target other AR domains. Although lead compounds have been identified, none have progressed into the clinic. Conclusions: Questions remain regarding the best approach for rationally designing new AR targeting therapeutics. Understanding how structural changes to the AR LBD lead to the failure of clinical therapeutics is a necessary step that should precede drug discovery campaigns. Moreover, computational modeling is a powerful tool that should be leveraged to streamline therapeutic development.<\/jats:p>","DOI":"10.3390\/cancers18061043","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:53:34Z","timestamp":1774274014000},"page":"1043","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Androgen Receptor Point Mutations: A Mechanism of Therapeutic Resistance and a Framework for Rational Drug Design"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3813-8949","authenticated-orcid":false,"given":"Avan","family":"Colah","sequence":"first","affiliation":[{"name":"Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2890-6528","authenticated-orcid":false,"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, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8032-857X","authenticated-orcid":false,"given":"Han","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"MacGillivray","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Chime, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, 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, QC J1H 5N4, 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, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.euo.2021.09.006","article-title":"Epidemiology and Prevention of Prostate Cancer","volume":"4","author":"Gandaglia","year":"2021","journal-title":"Eur. 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