{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T09:06:33Z","timestamp":1784797593026,"version":"3.55.0"},"reference-count":120,"publisher":"Portland Press Ltd.","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Nuclear receptors (NRs) are ligand-regulated transcription factors that control many physiological processes, from metabolism and inflammation to development and circadian rhythms. Beginning in the 1990s, systematic chemical probe development transformed many \u2018orphan\u2019 NRs with unknown endogenous ligands into chemically tractable, well-studied molecular targets, uncovering their physiological functions and potential for therapeutic development. The present review examines how small molecule ligands for peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor enabled the scientific community to connect orphan NR activation to specific transcriptional programs, metabolic phenotypes, and disease processes\u2014while emerging tools for liver receptor homolog-1\/steroidogenic factor-1, Rev-Erbs, nerve growth factor-induced clone Bs, HNF4, and transcription factor tailless hold promise to do likewise. These tools not only had widespread impact on NR biology but also established many design principles for chemical probes that continue to guide the field today. The NR field demonstrates how systematic chemical probe discovery can enable basic research and de-risk therapeutic hypotheses, providing a roadmap for other chemical probe initiatives in the human proteome.<\/jats:p>","DOI":"10.1042\/ebc20260016","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T08:47:53Z","timestamp":1784796473000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The enabling power of chemical probes: examples from the nuclear hormone receptor field"],"prefix":"10.1042","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4181-8223","authenticated-orcid":false,"given":"Timothy\u00a0M.","family":"Willson","sequence":"first","affiliation":[{"name":"1Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5359-8128","authenticated-orcid":false,"given":"Daniel","family":"Merk","sequence":"additional","affiliation":[{"name":"2Department of Pharmacy, Ludwig-Maximilians-Universit\u00e4t (LMU) M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"2026072304474657200_B1","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.cell.2014.03.012","article-title":"Nuclear receptors, RXR, and the big bang","volume":"157","author":"Evans","year":"2014","journal-title":"Cell"},{"key":"2026072304474657200_B2","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/0092-8674(95)90199-X","article-title":"The nuclear receptor superfamily: the second decade","volume":"83","author":"Mangelsdorf","year":"1995","journal-title":"Cell"},{"key":"2026072304474657200_B3","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1038\/nchembio.1867","article-title":"The promise and peril of chemical probes","volume":"11","author":"Arrowsmith","year":"2015","journal-title":"Nat. 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