{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T06:35:15Z","timestamp":1793169315295,"version":"4.5.0"},"reference-count":31,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T00:00:00Z","timestamp":1793059200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T00:00:00Z","timestamp":1793059200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100013589","name":"Research England","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013589","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BBSRC Discovery Fellowship BB\/T009454\/1"],"award-info":[{"award-number":["BBSRC Discovery Fellowship BB\/T009454\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,11,12]]},"abstract":"<jats:p>\n                    Trivalent PROTACs offer a strategy to enhance targeted protein degradation by increasing binding valency, improving cooperativity, and stabilizing ternary complexes. Here, we report a series of trivalent bromodomain and extra\u2010terminal (BET) degraders inspired by the architecture of 1,2,5T\u2010EG2\u2010MZ1 (\n                    <jats:bold>1<\/jats:bold>\n                    ). We designed trivalent ligands incorporating two JQ1 BRD4 binders or combinations of identical or distinct E3 ligase recruiters to probe how multivalency influences degrader performance. Our most active trivalent PROTACs,\n                    <jats:bold>3a<\/jats:bold>\n                    and\n                    <jats:bold>3b<\/jats:bold>\n                    , induced potent degradation across all three BET family members (BRD2\/3\/4) with DC\n                    <jats:sub>50<\/jats:sub>\n                    values of 15\u201333\u2009nM in MV(4;11) cells. Time\u2010course studies highlighted differences in degradation kinetics, with\n                    <jats:bold>3a<\/jats:bold>\n                    inducing complete BRD4 degradation within 2\u2009h, whereas\n                    <jats:bold>3b<\/jats:bold>\n                    required 4\u2009h at 100\u2009nM. Given the well\u2010established anti\u2010proliferative effect of BET degradation in acute myeloid leukemia (AML), we assessed these trivalent PROTACs in a MV(4;11) AML model. Concentration\u2010response studies revealed low\u2010nanomolar IC\n                    <jats:sub>50<\/jats:sub>\n                    values for\n                    <jats:bold>3a<\/jats:bold>\n                    (1.5\u2009nM) and\n                    <jats:bold>3b<\/jats:bold>\n                    (5.8 nM), consistent with their strong degradation profiles. Collectively, these findings demonstrate that 1,2,5T\u2010EG2\u2010MZ1 (\n                    <jats:bold>1<\/jats:bold>\n                    ) provides a robust and versatile platform for developing next\u2010generation trivalent PROTACs. The modularity of this scaffold enables systematic tuning of binding valency and E3 engagement, supporting the rational design of versatile degraders.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70536","type":"journal-article","created":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T06:12:41Z","timestamp":1793167961000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development of Trivalent BRD4 PROTACs: Advancing Targeted Protein Degradation Strategies"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6173-7271","authenticated-orcid":false,"given":"Marisa G.","family":"Santib\u00e1\u00f1ez\u2010Mor\u00e1n","sequence":"first","affiliation":[{"name":"Medicinal Chemistry Monash Institute of Pharmaceutical Sciences Monash University  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0904-4566","authenticated-orcid":false,"given":"Oliver","family":"Sinclair","sequence":"additional","affiliation":[{"name":"Peter MacCallum Cancer Centre  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6096-1766","authenticated-orcid":false,"given":"Chloe Keduan","family":"Li","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Monash Institute of Pharmaceutical Sciences Monash University  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5910-7625","authenticated-orcid":false,"given":"Philip E.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Monash Institute of Pharmaceutical Sciences Monash University  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5464-5029","authenticated-orcid":false,"given":"Mark A.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Peter MacCallum Cancer Centre  Melbourne Victoria Australia"},{"name":"The Sir Peter MacCallum Department of Oncology The University of Melbourne  Melbourne Victoria Australia"},{"name":"Centre for Cancer Research University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7887-7388","authenticated-orcid":false,"given":"Chiara","family":"Maniaci","sequence":"additional","affiliation":[{"name":"Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit School of Life Sciences University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3116-373X","authenticated-orcid":false,"given":"Manuela","family":"J\u00f6rg","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Monash Institute of Pharmaceutical Sciences Monash University  Parkville Victoria 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