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FDA\u2010approved and investigational glue and degrader drugs function by recruiting a POI to an E3 ubiquitin ligase that mediates POI polyubiquitination and triggers proteasomal degradation. However, using E3 ligases as an intermediary and requiring POI polyubiquitination makes this mechanism of action complex and difficult to rationalize and optimize. These issues have led to interest in evaluating whether direct recruitment of non\u2010ubiquitinated POIs to the proteasome might achieve the same pharmacological outcome. Here, we examined the potential of direct\u2010to\u2010proteasome non\u2010ubiquitinated POI recruitment. Using a tag strategy, we first demonstrated that the proteasomal 19S cap region proteins, RPN13 and RPN1, can recruit non\u2010ubiquitinated POI model proteins, such as BRD4, to the proteasome and induce degradation. Subsequently, we developed small molecule\u2010based bifunctional recruiter molecules (Proteasome Cap Targeting Chimeras, CAP\u2010TACs) and showed that they recruit several distinct POIs, including BRD4, PRMT5, and FKBP12, to specific subunits in the 19S cap region and induce their ubiquitination\u2010independent, proteasome\u2010dependent degradation. This study provides further evidence that bifunctional small molecules can re\u2010localize POIs to the proteasome and induce their degradation in the absence of ubiquitination, which broadens the capabilities of targeted protein degradation.<\/jats:p>","DOI":"10.1002\/anie.202520039","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T13:12:48Z","timestamp":1768914768000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Proteasome Cap Targeting Chimeras for Ubiquitination\u2010Independent Targeted Protein Degradation"],"prefix":"10.1002","volume":"65","author":[{"given":"Chen","family":"Song","sequence":"first","affiliation":[{"name":"Department of Cancer Biology Dana\u2010Farber Cancer Institute  Boston MA USA"},{"name":"Department of Medicine Harvard Medical School  Boston MA 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