{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T19:17:38Z","timestamp":1772997458557,"version":"3.50.1"},"reference-count":98,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The estrogen receptor is a central mediator of estrogen\u2010driven gene expression, influencing a wide array of physiological processes. Conventional endocrine therapies, including selective estrogen receptor modulators (SERMs) and degraders (SERDs), often face limitations due to acquired resistance and reduced efficacy in ER\u03b1\u2010mutant cancers. Proteolysis\u2010targeting chimeras (PROTACs) serve as a next\u2010generation therapeutic strategy designed to selectively and efficiently degrade estrogen receptor alpha (ER\u03b1). The approval of elacestrant further expanded interest in developing novel ER\u03b1 degraders, shifting the paradigm of drug discovery in this area. This review highlights the mechanism of action of PROTACs, structural and functional domains of ER\u03b1, design of PROTACs, and their application in targeting the ER\u03b1 receptor. Special emphasis is also given on structure activity relationship (SAR) studies and strategies of designing PROTACs reported in the literature, along with in vitro and in vivo studies data. Collectively, these strategies provide valuable insights for designing effective PROTACs to overcome endocrine resistance and advance therapeutic options in ER\u03b1\u2010positive breast cancers.<\/jats:p>","DOI":"10.1002\/ardp.70176","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T10:01:13Z","timestamp":1766484073000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protacs Targeting ER\u03b1 in the Effective Management of Endocrinal Resistance Breast Cancer"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1900-9640","authenticated-orcid":false,"given":"Anupriya","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences Central University of Punjab Bathinda Punjab India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8218-5193","authenticated-orcid":false,"given":"Roshni","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences Central University of Punjab Bathinda Punjab India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7957-9998","authenticated-orcid":false,"given":"Noora Amana","family":"Erachampatt","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences Central University of Punjab Bathinda Punjab India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0416-8543","authenticated-orcid":false,"given":"Neha","family":"Bhatia","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences Central University of Punjab Bathinda Punjab India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4004-6241","authenticated-orcid":false,"given":"Vikramdeep","family":"Monga","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences Central University of Punjab Bathinda Punjab India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7668-462X","authenticated-orcid":false,"given":"Suresh","family":"Thareja","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Natural Products, School of Health Sciences Central University of Punjab Bathinda Punjab India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"issue":"2","key":"e_1_2_16_2_1","first-page":"171","article-title":"Breast Cancer Treatment","volume":"104","author":"Trayes K. P.","year":"2021","journal-title":"American Family Physician"},{"key":"e_1_2_16_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2025.01.014"},{"key":"e_1_2_16_4_1","unstructured":"D.Stephan Prevalence of Breast Cancer Subtypes and Outcome In Metastatic Breast Cancer Patients Diagnosed Between 1984 and 2020."},{"key":"e_1_2_16_5_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-14-0092"},{"key":"e_1_2_16_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22157812"},{"key":"e_1_2_16_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.19323"},{"key":"e_1_2_16_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112689"},{"key":"e_1_2_16_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2012.04413.x"},{"key":"e_1_2_16_10_1","doi-asserted-by":"publisher","DOI":"10.1677\/erc.1.00857"},{"key":"e_1_2_16_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b01572"},{"key":"e_1_2_16_12_1","doi-asserted-by":"publisher","DOI":"10.2174\/1871520620666200410082652"},{"key":"e_1_2_16_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2024.176424"},{"key":"e_1_2_16_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.82.12.4470"},{"key":"e_1_2_16_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0039-128X(00)00143-4"},{"key":"e_1_2_16_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115422"},{"key":"e_1_2_16_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2018.10.020"},{"key":"e_1_2_16_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109180108"},{"key":"e_1_2_16_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.463455"},{"key":"e_1_2_16_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)01548-0"},{"key":"e_1_2_16_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80259-2"},{"key":"e_1_2_16_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.9.4037"},{"key":"e_1_2_16_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.32345"},{"key":"e_1_2_16_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-1171"},{"key":"e_1_2_16_25_1","doi-asserted-by":"publisher","DOI":"10.3109\/02841868809090312"},{"key":"e_1_2_16_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(61)91088-1"},{"key":"e_1_2_16_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-1-4832-2903-4.50009-X"},{"key":"e_1_2_16_28_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197911013011826"},{"key":"e_1_2_16_29_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568026618666181010101922"},{"key":"e_1_2_16_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00371-6"},{"key":"e_1_2_16_31_1","doi-asserted-by":"publisher","DOI":"10.37349\/etat.2020.00018"},{"key":"e_1_2_16_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242216346"},{"key":"e_1_2_16_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature00767"},{"key":"e_1_2_16_34_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1073440"},{"key":"e_1_2_16_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1177319"},{"key":"e_1_2_16_36_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4CS00411F"},{"key":"e_1_2_16_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.9b00597"},{"key":"e_1_2_16_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100647"},{"key":"e_1_2_16_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10092100"},{"key":"e_1_2_16_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.141230798"},{"key":"e_1_2_16_41_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00148A"},{"key":"e_1_2_16_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-019-0362-y"},{"key":"e_1_2_16_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2329"},{"key":"e_1_2_16_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.4c00189"},{"key":"e_1_2_16_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2024.04.007"},{"key":"e_1_2_16_46_1","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20170041"},{"key":"e_1_2_16_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2019.08.001"},{"key":"e_1_2_16_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1858"},{"key":"e_1_2_16_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.9b00397"},{"key":"e_1_2_16_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-023-02905-1"},{"key":"e_1_2_16_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.0c06362"},{"key":"e_1_2_16_52_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2002-0269"},{"key":"e_1_2_16_53_1","unstructured":"M.Mazaheri Molecular Basis of Anti\u2010Hormonal Treatment and Resistance in Breast Cancer. Universit\u00e9 de Toulouse Universit\u00e9 Toulouse III\u2010Paul Sabatier 2009."},{"key":"e_1_2_16_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)42154-0"},{"key":"e_1_2_16_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1028-4559(08)60051-0"},{"key":"e_1_2_16_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2015.117"},{"key":"e_1_2_16_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2823"},{"key":"e_1_2_16_58_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c02032"},{"key":"e_1_2_16_59_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12081801"},{"key":"e_1_2_16_60_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-18-1129"},{"key":"e_1_2_16_61_1","doi-asserted-by":"publisher","DOI":"10.3390\/bioengineering10121368"},{"key":"e_1_2_16_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-021-00878-4"},{"key":"e_1_2_16_63_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00649"},{"key":"e_1_2_16_64_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c00740"},{"key":"e_1_2_16_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.290"},{"key":"e_1_2_16_66_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.98450.3"},{"key":"e_1_2_16_67_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4OB00304G"},{"key":"e_1_2_16_68_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.16_suppl.TPS1120"},{"key":"e_1_2_16_69_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2021-43"},{"key":"e_1_2_16_70_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-025-01137-5"},{"key":"e_1_2_16_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.03.058"},{"key":"e_1_2_16_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.09.005"},{"key":"e_1_2_16_73_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2019.37.7_suppl.259"},{"key":"e_1_2_16_74_1","article-title":"A Phase 2 Expansion Study of ARV\u2010766, a PROTAC Androgen Receptor (AR) Degrader, in Metastatic Castration\u2010Resistant Prostate Cancer (mCRPC)","volume":"1","author":"Petrylak D. P.","year":"2023","journal-title":"American Society of Clinical Oncology"},{"key":"e_1_2_16_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-022-01296-8"},{"key":"e_1_2_16_76_1","unstructured":"Sanofi A Phase 2 Study to Evaluate the Efficacy and Safety of SAR444656 Compared With Placebo in Adult Participants With Moderate to Severe Hidradenitis Suppurativa (ZEN) https:\/\/clinicaltrials.gov\/study\/NCT06028230?intr=NCT06028230&rank=1."},{"key":"e_1_2_16_77_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-179872"},{"key":"e_1_2_16_78_1","unstructured":"Novartis Pharmaceuticals Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors https:\/\/www.clinicaltrials.gov\/study\/NCT03891953?utm_source=chatgpt.com."},{"key":"e_1_2_16_79_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.T300009-MCP200"},{"key":"e_1_2_16_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201000146"},{"key":"e_1_2_16_81_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic"},{"key":"e_1_2_16_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2003.11.042"},{"key":"e_1_2_16_83_1","doi-asserted-by":"publisher","DOI":"10.2174\/1386207043328364"},{"key":"e_1_2_16_84_1","unstructured":"G.Luo X.Li X.Lin X.Lu Z.Li andH.Xiang Novel 11\u03b2\u2010Substituted Estradiol Conjugates: Transition From Er\u03b1 Agonists to Potent Protac Degraders. Available at SSRN 4025200."},{"key":"e_1_2_16_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2023.117526"},{"key":"e_1_2_16_86_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00196"},{"key":"e_1_2_16_87_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2021-44"},{"key":"e_1_2_16_88_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01186"},{"key":"e_1_2_16_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116972"},{"key":"e_1_2_16_90_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01521"},{"key":"e_1_2_16_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2025.118111"},{"key":"e_1_2_16_92_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.7b00985"},{"key":"e_1_2_16_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.111967"},{"key":"e_1_2_16_94_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.9b00025"},{"key":"e_1_2_16_95_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.0c00140"},{"key":"e_1_2_16_96_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114770"},{"key":"e_1_2_16_97_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.116184"},{"key":"e_1_2_16_98_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.AC119.010790"},{"key":"e_1_2_16_99_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.1c00629"}],"container-title":["Archiv der Pharmazie"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ardp.70176","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ardp.70176","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ardp.70176","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:26:50Z","timestamp":1772987210000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ardp.70176"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":98,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/ardp.70176"],"URL":"https:\/\/doi.org\/10.1002\/ardp.70176","archive":["Portico"],"relation":{},"ISSN":["0365-6233","1521-4184"],"issn-type":[{"value":"0365-6233","type":"print"},{"value":"1521-4184","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-09-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70176"}}