Targeted Protein Degradation Strategies in Drug Discovery

Targeted protein degradation harnesses cellular quality-control pathways to eliminate disease-causing proteins rather than merely inhibit their function. Central to this approach are bifunctional molecules or “degraders” that bridge a protein of interest with an E3 ubiquitin ligase, triggering ubiquitination and subsequent proteasomal clearance. Proteolysis-targeting chimeras (PROTACs) exemplify this paradigm, combining a ligand for the target protein with a ligand for an E3 ligase via a chemical linker. In parallel, molecular glues act as monovalent adaptors that stabilise transient interactions between E3 ligases and substrates. Beyond the proteasome, emerging platforms such as lysosome-targeting chimaeras (LYTACs) and antibody-based degraders extend the scope to extracellular or membrane proteins. These strategies offer unprecedented access to previously “undruggable” targets, enable catalytic modes of action, and show promising efficacy in oncology, immunology and beyond. Challenges remain in achieving tissue specificity, optimising pharmacokinetics and minimising off-target degradation, yet the field has already delivered early clinical proof of concept and a pipeline of next-generation degraders.

Research from Nature Portfolio

A first-in-human trial of an IRAK4 degrader demonstrated potent, dose-dependent degradation of interleukin-1 receptor-associated kinase 4 in blood and lesional skin of patients with inflammatory skin disorders, with associated biomarker modulation and clinical improvement, establishing safety and proof of concept for heterobifunctional degraders in immunodermatology. Separately, the design of isoform-selective PROTACs against p38 mitogen-activated protein kinase illustrated how variations in linker geometry and ternary complex orientation dictate selective recruitment of the VHL E3 ligase, enabling degradation of either p38α or p38δ. This work provides a mechanistic framework for achieving target family selectivity through fine-tuning of degrader architecture.

Targeted Protein Degradation Strategies in Drug Discovery publication trend

The graph below shows the total number of articles in targeted protein degradation strategies in drug discovery across all publications each year (not limited to Nature Index journals).

Technical terms

Proteolysis-targeting chimera (PROTAC): A bifunctional molecule that recruits an E3 ubiquitin ligase to a target protein to induce its ubiquitination and proteasomal degradation.

Molecular glue: A monovalent small molecule that stabilises or induces a direct interaction between an E3 ubiquitin ligase and a substrate protein, leading to substrate ubiquitination and degradation.

Ternary complex: The three-component assembly comprising the target protein, degrader molecule and E3 ubiquitin ligase, essential for catalysing ubiquitination.

E3 ubiquitin ligase: An enzyme that recognises specific substrates and catalyses the transfer of ubiquitin, marking proteins for degradation by the proteasome.

References

1. Targeted protein degradation: advances in drug discovery and clinical practice. Signal Transduction and Targeted Therapy (2024).
2. Covalent Proximity Inducers. Chemical Reviews (2024).
3. IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial. Nature Medicine (2023).
4. Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4. ACS Chemical Biology (2015).
5. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nature Communications (2019).