{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T17:36:54Z","timestamp":1791567414725,"version":"4.3.4"},"reference-count":192,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The onset of proteolysis targeting chimeras (PROTACs) has reshaped the entire context of targeted cancer therapy by offering a novel approach for the selective degradation of disease-causing proteins, overcoming the limitations of traditional occupancy-driven inhibition. This heterobifunctional technology recruits endogenous E3 ubiquitin ligases to mark proteins of interest (POI) for proteosomal degradation via the ubiquitin-proteasome system (UPS). Unlike conventional inhibitors, PROTACs function catalytically and can target previously \u201cundruggable proteins\u201d, such as transcription factors, scaffold proteins, and non-enzymatic regulators, offering potential to overcome acquired resistance and achieve potent efficacy at sub-stoichiometric doses. The review explores the latest innovations in PROTAC design, including E3 ligase selection, linker chemistry, and ligand optimization, while highlighting promising preclinical and clinical candidates against oncogenic drivers, anti-apoptotic factors (BCL-xL), and nuclear hormone receptors. Furthermore, we critically examine key translational challenges, such as pharmacokinetics, off-target effects, and resistance mechanisms, and discuss viable solutions, including dual E3 ligase engagement, novel modalities like AUTACs\/ATTECs, LYTACs, and AI-driven design. As the field rapidly evolves from foundational to clinical application, PROTACs are redefining therapeutic possibilities, offering a robust, flexible, and scalable framework for the future of precision oncology.<\/jats:p>","DOI":"10.3390\/biom16020325","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T15:57:29Z","timestamp":1771516649000},"page":"325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Targeted Protein Degradation in Cancer: PROTACs, New Targets, and Clinical Mechanisms"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6813-9249","authenticated-orcid":false,"given":"Bushra","family":"Faryal","sequence":"first","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6815-514X","authenticated-orcid":false,"given":"Zain","family":"Ul Abideen","sequence":"additional","affiliation":[{"name":"Department of Biosciences, COMSATS University Islamabad, Islamabad 45550, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1265-2765","authenticated-orcid":false,"given":"Muhammad","family":"Irfan","sequence":"additional","affiliation":[{"name":"Department of Biosciences, COMSATS University Islamabad, Islamabad 45550, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haseeb","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Biosciences, COMSATS University Islamabad, Islamabad 45550, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fazliddin","family":"Jalilov","sequence":"additional","affiliation":[{"name":"The Department of Pharmaceutical and Chemistry, Alfraganus University, Tashkent 100190, Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lola","family":"Abduraximova","sequence":"additional","affiliation":[{"name":"Kimyo International University in Tashkent, Shota Rustaveli str. 156, Tashkent 100121, Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9839-4121","authenticated-orcid":false,"given":"Ghulam Abbas","family":"Ashraf","sequence":"additional","affiliation":[{"name":"Low Dimensional Materials Research Center, Khazar University, Baku AZ1096, Azerbaijan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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