{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:48:24Z","timestamp":1792003704267,"version":"4.4.0"},"reference-count":16,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100006692","name":"University of Turin in Italy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006692","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":[[2026,10,14]]},"abstract":"<jats:p>Targeted protein degradation has emerged as a clinically validated therapeutic strategy, culminating in the recent FDA approval of the first proteolysis\u2010targeting chimeras (PROTAC) drug (VEPPANU). Within PROTACs, the linker plays a central role in modulating degradation efficiency as well as physicochemical and in vitro absorption, distribution, metabolism, and excretion properties, yet linker optimization still largely relies on empirical \u201clinkerology\u201d approaches. Here, we investigated whether simple 2D linker descriptors could provide informative insights for very early\u2010stage PROTAC design. Four matched PROTAC series, including both cereblon\u2010 and von Hippel\u2013Lindau\u2010recruiting degraders, were retrospectively analyzed using a workflow combining the in\u2010house Bellerophon\u2010based linker extraction with principal component analysis. Selected descriptors captured linker hydrophobicity, polarity, flexibility, and topology and were correlated with experimental degradation, permeability, solubility, lipophilicity, protein binding, and metabolic stability data. In several datasets, linker\u2010dependent trends associated with the molecular properties of degraders and their degradation efficiency were identified, particularly for von Hippel\u2013Lindau\u2010based PROTACs. Although the limited size of currently available datasets prevents broad generalization, this work highlights the potential of simple descriptor\u2010based analyses to support early candidate prioritization and reduce unnecessary synthetic efforts.<\/jats:p>","DOI":"10.1002\/cmdc.70532","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T06:30:49Z","timestamp":1791786649000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Limiting Trial\u2010and\u2010Error: Linker\u2010Based 2D Descriptor Analysis to Support Very Early Proteolysis\u2010Targeting Chimeras Design"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6906-2849","authenticated-orcid":false,"given":"Giulia","family":"Apprato","sequence":"first","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Turin  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2713-9624","authenticated-orcid":false,"given":"Serena","family":"Traversa","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Turin  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2417-5900","authenticated-orcid":false,"given":"Giulia","family":"Caron","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Turin  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3710-3102","authenticated-orcid":false,"given":"Giuseppe","family":"Ermondi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Turin  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2017.05.024"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/pharmtox.2017.57.issue\u20101"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573\u2010026\u201000078\u20106"},{"issue":"5","key":"e_1_2_9_5_1","first-page":"273","article-title":"Current Strategies for the Design of PROTAC Linkers: A Critical Review","volume":"1","author":"Troup R. I.","year":"2020","journal-title":"Open Exploration"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2329"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.1c00298"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00877"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c00740"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010021\u201000371\u20106"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c02492"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c00718"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01305"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c00851"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.5c00769"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.3c00231"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26030672"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70532","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.70532","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70532","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:08:34Z","timestamp":1792001314000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.70532"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,11]]},"references-count":16,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2026,10,14]]}},"alternative-id":["10.1002\/cmdc.70532"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.70532","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,11]]},"assertion":[{"value":"2026-06-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70532"}}