{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:13:22Z","timestamp":1792790002753,"version":"4.5.0"},"reference-count":153,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R21CA273399"],"award-info":[{"award-number":["R21CA273399"]}]},{"name":"DoD","award":["OCRP HT9425-23-1-0238"],"award-info":[{"award-number":["OCRP HT9425-23-1-0238"]}]},{"name":"Nebraska DHHS","award":["LB506"],"award-info":[{"award-number":["LB506"]}]},{"name":"the Betty J. and Charles D. McKinsey Ovarian Cancer Research Fund","id":[{"id":"https:\/\/ror.org\/05hg41718","id-type":"ROR","asserted-by":"crossref"}]},{"name":"the Fred & Pamela Buffett Cancer Center","award":["NIH 5P30CA036727"],"award-info":[{"award-number":["NIH 5P30CA036727"]}],"id":[{"id":"https:\/\/ror.org\/03n63wv08","id-type":"ROR","asserted-by":"crossref"}]},{"award":["NIH 5P30CA036727"],"award-info":[{"award-number":["NIH 5P30CA036727"]}],"id":[{"id":"https:\/\/ror.org\/03n63wv08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Hydrophobic tag degraders (HyTDs) are a promising strategy for achieving targeted protein degradation (TPD). HyTDs are composed of a hydrophobic moiety conjugated via a linker to a ligand that binds to the protein of interest (POI). Binding induces a surface-exposed hydrophobic patch that mimics a misfolded protein, triggering degradation through the cell\u2019s diverse quality-control networks, including the ubiquitin-proteasome system (UPS), ubiquitin-independent proteasome degradation (UbInPD), the autophagy-lysosome pathway (ALP), and the unfolded protein response (UPR). This distinct multi-pathway mechanism distinguishes HyTDs from traditional TPD strategies such as PROTACs and molecular glue degraders (MGDs), which rely on a narrow pool of specific E3 ligases. The effectiveness of HyTDs is influenced by the chemical properties of the hydrophobic moiety, the linker, and the ligand\u2019s binding kinetics to the POI. To date, several relevant cancer targets, including the androgen receptor (AR), AKT serine\/threonine kinase 3 (Akt3), and enhancer of zeste homolog 2 (EZH2), have been successfully targeted using HyTDs. Gaining deeper mechanistic insight into the nature of HyT degradation will be essential to further the potential of HyTDs as powerful tools in cancer research and therapeutics.<\/jats:p>","DOI":"10.3390\/ph19091477","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hydrophobic Tag Protein Degraders: An Emerging Therapeutic Strategy for Cancer"],"prefix":"10.3390","volume":"19","author":[{"given":"Tania","family":"Aguilera-Pineda","sequence":"first","affiliation":[{"name":"Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"The Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6794-2794","authenticated-orcid":false,"given":"Siddhartha","family":"Kumar","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8399-5354","authenticated-orcid":false,"given":"Gargi","family":"Ghosal","sequence":"additional","affiliation":[{"name":"The Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5067-0203","authenticated-orcid":false,"given":"Amarnath","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, James L. 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