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Targeted Protein Degradation
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# Targeted Protein Degradation Portal: Future Pharma Stage: Clinical trials advancing Evidence: Early human Template: Drug platform Risk: Moderate Reversibility: Reversible Last reviewed: May 2026 == Summary == Instead of blocking a protein, degraders instruct the cell to destroy it — expanding the range of disease targets beyond what traditional inhibitors can reach. == Key takeaways == * Degraders recruit the cell's disposal machinery to eliminate a target protein rather than merely inhibit it. * This can reach 'undruggable' proteins that lack a good inhibitor binding pocket. * A single degrader molecule can act repeatedly, and it removes all of a protein's functions at once. == Mechanism == A bifunctional degrader binds the target protein at one end and an E3 ubiquitin ligase at the other, tagging the target for destruction by the proteasome. Molecular glues achieve a similar outcome with smaller molecules that reshape a protein surface to recruit degradation. Because the degrader acts catalytically and eliminates the whole protein, it can silence functions that an inhibitor blocking a single active site would miss — useful for scaffolding proteins and transcription factors long considered undruggable. == Clinical direction == Oral degraders targeting hormone receptors and blood-cancer drivers have advanced through clinical trials, with oncology leading. The modality's promise is reaching targets that resisted decades of inhibitor development. Challenges include oral bioavailability of large molecules, selectivity across the many E3 ligases, and the consequences of removing a protein entirely rather than tuning it. The field is early but has moved from concept to credible pipeline. == Open questions == * Which E3 ligases give tissue-selective degradation? * When is total removal of a protein safer or riskier than partial inhibition? == Watchlist == * Oral degrader bioavailability * New E3 ligase recruiters * Resistance mechanisms == References == * Targeted protein degradation review — Békés, Langley & Crews, Nature Reviews Drug Discovery, 2022. https://pubmed.ncbi.nlm.nih.gov/35042991/. Comprehensive review of PROTACs, molecular glues, and clinical progress. == Categories == [[Category:Future Pharma]] [[Category:PROTAC]] [[Category:molecular glue]] [[Category:drug modality]]