Hijacking the Cell’s Disposal System: Targeted Protein Degradation

Hijacking the Cell’s DISPOSALSYSTEM: Targeted Protein Degradation UnDrUgGaBlE PrOtEiNs For decades, drug discovery focused on blocking protein activity with inhibitors, which require well-defined binding sites that many proteins lack. Targeted protein degradation (TPD) is a revolutionary strategy that overcomes this by redirecting the cell’s own disposal system to remove proteins, enabling previously “undruggable” targets to be tackled. This infographic shows how protein degradation machinery can be hijacked to achieve therapeutic effects and highlights advances in the field. CELLULAR MACHINERY As part of their protein quality control system, cells use the ubiquitin–proteasome system to degrade unwanted proteins. During this process, an E3 ligase binds to a target protein (TP) and mediates the transfer of ubiquitin onto the TP via an E2 carrier, marking it for proteasomal degradation. TPD leverages this pathway, recruiting the cell’s own machinery to tag pathogenic proteins for destruction. Two major TPD modalities include molecular glues (MGs) and proteolysis targeting chimeras (PROTACs). MOLECULAR GLUES Pomalidomide MGs are small molecules that bind to either the TP or the E3 ligase, inducing changes that promote protein–protein interactions between the ligase and TP. This triggers the attachment of ubiquitin chains to the TP. Three MGs are FDA-approved: thalidomide, lenalidomide, and pomalidomide, all classed as immunomodulatory imide drugs (IMiDs). A classic example, thalidomide, was first marketed for morning sickness in the 1950s and was soon withdrawn after causing birth defects. It inspired the development of more potent analogs, which are now used to treat multiple myeloma by degrading transcription factors essential for cell proliferation. Lenalidomide Thalidomide E3 MG TP PROTACs PROTACs are heterobifunctional molecules, with each end binding to either the TP or the E3 ligase to create a ternary complex. The resulting proximity between the TP and E3 ligase drives TP ubiquitination. PROTACs have evolved from early peptide-based prototypes to small-molecule candidates. In 2019, they entered clinical trials for breast cancer. MGs and PROTACs can also work in combination. For example, thalidomide and its analogues have been utilized as E3 ligase-recruiting ligands in PROTACs. RECENT ADVANCES IN TPD DRUG DEVELOPMENT New developments focus on enhancing the physicochemical properties of PROTACs, minimizing off-target degradation of MGs, and optimizing overall therapeutic efficacy. 2001 Present TP E3 Virtual screening MG ALTERNATIVE E3 LIGASE RECRUITMENT Expanding beyond CRBN/VHL to new ligases helps overcome resistance and reach more tissues. MACROCYCLIC CONFORMATIONS Altered conformation could increase stability, selectivity, potency, and permeability. DUAL AND TRIVALENT SYSTEMS Multi-target degradation reduces drug resistance and enhances efficacy. HTS AND AI-DRIVEN DESIGN These approaches could accelerate discovery through prediction and optimization. TARGETING NON-CANONICAL INTERACTIONS Expands the scope of targets across multiple diseases. PHOTO-SWITCHABLE DEGRADERS Light-controlled, precise degradation results in fewer off-target effects. OTHER INNOVATIONS INCLUDE: Using rigid PROTAC linkers Substituting IMiDs with phenyl glutarimide (PG) as CRBN ligands Exploiting lysosomal and autophagy pathways Exploring polyvalent natural products Repurposing non-degrading inhibitors DELIVERY METHODS Nanoparticles, liposomes, and targeted carriers boost solubility and tumor penetration. Ubiquitin ligase complex TP Ub E3 E2 WRITTEN BY: GEORGINA DAVIES DESIGNED BY: ERIN LEMIEUX TPD represents a transformative shift in drug discovery, moving beyond inhibition to the selective removal of previously “undruggable” disease-causing proteins. Innovations are addressing longstanding challenges and expanding the degradable proteosome, paving the way for more effective, highly selective treatments across a broad spectrum of diseases. Proteasome