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PROTACs trigger catalytic and sub-stoichiometric degradation of the target protein in contrast with stoichiometric, occupancy-based inhibition. Because of this distinct mode of action, PROTACs overcome key limitations of inhibitors, including incomplete functional suppression, the requirement for sustained target occupancy, and poor selectivity within conserved protein families. PROTAC activity depends on multiple factors, including cell permeability, binary target engagement, ternary complex formation, stability and cooperativity, and efficiency of ubiquitination and degradation. Robust evaluation of PROTAC chemical probes therefore requires systematic assessment of potency, degradation kinetics, mechanistic validation, and selectivity profiling. Advances in mechanistic understanding have positioned PROTACs as versatile chemical probes that enable precise and temporally controlled protein depletion, offering unique opportunities for target validation, pathway dissection, and drug discovery. Recent case studies demonstrate clinical and preclinical PROTACs targeting previously undruggable proteins, highlighting the potential of degradation strategies, while emerging modalities such as molecular glues and proximity-inducing molecules further broaden the landscape of protein regulation.<\/jats:p>","DOI":"10.1042\/ebc20260006","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T08:39:09Z","timestamp":1790239149000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fitness criteria for PROTACs as chemical probes: principles and applications"],"prefix":"10.1042","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4026-2211","authenticated-orcid":false,"given":"Manon","family":"Sturbaut","sequence":"first","affiliation":[{"name":"Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, 1 James Lindsay Place, Dundee DD1 5JJ, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8654-1670","authenticated-orcid":false,"given":"Alessio","family":"Ciulli","sequence":"additional","affiliation":[{"name":"Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, 1 James Lindsay Place, Dundee DD1 5JJ, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"2026092404390148400_B1","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.chembiol.2010.05.013","article-title":"Probing the probes: fitness factors for small molecule tools","volume":"17","author":"Workman","year":"2010","journal-title":"Chem. 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