Targeted Protein Degradation

Don't block the bad protein — tag it for the cell's own shredder.

Classic drugs inhibit a protein by plugging its active site — which only works if the protein has a pocket to plug. Degraders take a different route: they recruit the cell's natural disposal system (an E3 ubiquitin ligase) to tag the target for destruction in the proteasome.

Because one degrader can mark many copies then move on (it's catalytic), and because it only needs to bind rather than block, this opens 'undruggable' targets. Molecular glues are small and drug-like; PROTACs are larger two-headed molecules. Poland's Captor Therapeutics is a credible player.

How it works in depth

Conventional drugs occupy a protein's active site and block it. Targeted protein degradation (TPD) instead destroys the protein outright by hijacking the cell's own quality-control machinery, the ubiquitin-proteasome system. The dominant approaches are PROTACs (proteolysis-targeting chimeras), bifunctional molecules with one end binding the target protein and the other recruiting an E3 ubiquitin ligase such as cereblon or VHL, and molecular glues, smaller single-binding compounds that reshape an E3 surface to create a new contact with the target. Either way, the target gets tagged with ubiquitin and shuttled to the proteasome for shredding. Because the degrader is released afterward and acts again, it is catalytic rather than stoichiometric, and it can hit "undruggable" proteins that lack a deep binding pocket, including transcription factors and scaffolding proteins.

Where the field is in 2025-2026

The field crossed a key threshold. In March 2025 Arvinas and Pfizer reported positive topline results from the Phase 3 VERITAC-2 trial of vepdegestrant (ARV-471), an oral estrogen-receptor PROTAC, the first PROTAC ever tested in Phase 3. It improved progression-free survival versus fulvestrant in the ESR1-mutant subgroup of pretreated ER+/HER2- advanced breast cancer; the data were presented at ASCO 2025 and published in the New England Journal of Medicine. Reportedly an NDA was submitted in 2025 with FDA review ongoing. On the molecular-glue side, the validated IMiD/CELMoD lineage (lenalidomide, pomalidomide) is being extended by next-generation cereblon glues. Open debates remain around oral bioavailability of large bifunctional molecules, the "hook effect," potential resistance via E3-ligase loss, and durability of degrader benefit.

Leading programs & players

Arvinas (with Pfizer) leads with vepdegestrant and is advancing ARV-393, a BCL6 degrader for B-cell lymphomas. Kymera Therapeutics is developing STAT6 degrader KT-621 and, with Sanofi, the IRAK4 degrader KT-474, oriented toward immunology. Bristol Myers Squibb, anchored by its 2019 Celgene acquisition, dominates molecular glues with the CELMoDs iberdomide, mezigdomide, and golcadomide; mezigdomide is in Phase 3 (SUCCESSOR-1/-2) for relapsed/refractory multiple myeloma, with possible first approval reportedly around 2026-2027. C4 Therapeutics and Nurix Therapeutics round out the dedicated degrader field. The market outlook is bullish but unproven commercially: a first PROTAC approval would be a watershed, and large pharma deals signal confidence that degradation can reach targets small-molecule inhibitors never could.

FAQ

What is the difference between a PROTAC and a molecular glue?

A PROTAC is a larger bifunctional molecule with two binding ends, one for the target protein and one for an E3 ligase, joined by a linker. A molecular glue is a smaller, single-site compound that reshapes an E3 ligase surface so it grips a target it normally ignores. Both end with the target being ubiquitinated and degraded.

Has any targeted protein degrader been approved by the FDA?

Molecular glues in the IMiD/CELMoD class, such as lenalidomide, have long been used in multiple myeloma, though their degrader mechanism was understood only later. As of 2025-2026 no purpose-designed PROTAC has been approved; Arvinas and Pfizer's vepdegestrant is the most advanced, reportedly under FDA review after positive Phase 3 VERITAC-2 data.

Why is targeted protein degradation called a way to drug the 'undruggable'?

Many disease-driving proteins, like transcription factors, lack a deep pocket for a classic inhibitor to occupy. Degraders only need to bind the target transiently to tag it for destruction, so they can act on flatter or non-enzymatic surfaces that traditional small molecules cannot block.

Which companies lead targeted protein degradation?

Arvinas (partnered with Pfizer) leads in PROTACs, Kymera focuses on immunology degraders, and Bristol Myers Squibb dominates cereblon molecular glues with iberdomide, mezigdomide, and golcadomide. C4 Therapeutics and Nurix are other dedicated players in the space.

Companies working on Targeted Protein Degradation

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