A milestone FDA approval and striking Phase 3 data presented this week at ASCO have put targeted protein degradation firmly in the spotlight. After two decades in the making, the science is finally delivering at the bedside.

For most of the history of drug discovery, medicine has worked by blocking things. A small molecule wedges itself into a protein’s active site and prevents it from functioning. An antibody binds to a receptor on a cell’s surface and stops a signal from getting through. The principle is one of competitive inhibition: occupy the target, disrupt the process, treat the disease. It is an elegant strategy, and it has produced some of the most important medicines ever made.

It has also, by definition, left a vast portion of the human proteome untouched. More than 70% of the proteins expressed in human cells lack the kind of well-defined active site into which a drug molecule can usefully fit. These proteins, long classified as undruggable, include many of the drivers of cancer, neurodegeneration and inflammatory disease. Transcription factors, scaffolding proteins, splicing regulators: all implicated in serious illness, all essentially immune to conventional pharmacology.

Targeted protein degradation offers a fundamentally different answer. Rather than blocking a disease-causing protein, it destroys it entirely. And in 2026, this approach has moved from a compelling scientific concept to a clinically validated drug class, with consequences that are beginning to reshape oncology.

How Degraders Work

The foundational insight dates to 2001, when Craig Crews at Yale and Raymond Deshaies proposed the first proteolysis-targeting chimera, or PROTAC. The molecular mechanism of PROTAC is to degrade the target protein through the ubiquitin-proteasome system, rather than inhibiting protein function through competitive binding to block the functional region of the target protein. Because the binding region recognised by PROTAC for the target protein does not have to be an active region, some previously undruggable proteins that lack high-affinity small molecule binding sites can become tractable.

The mechanism is elegantly catalytic. A PROTAC molecule is bifunctional: one end binds the target protein, the other recruits an E3 ubiquitin ligase, one of the cell’s own protein-tagging enzymes. PROTACs enlist client proteins and E3 ubiquitin ligase complexes into proximity, thereby triggering the ubiquitination and subsequent degradation of the client protein. Their recyclable, event-driven mechanism allows for efficient clearance at low doses and enables the targeting of proteins that are inaccessible to classical small-molecule inhibitory molecules.

Crucially, once the target protein has been tagged and sent to the proteasome for destruction, the PROTAC molecule is released and can repeat the cycle. A single degrader molecule can eliminate many copies of the target protein, which means effective doses can be substantially lower than those required for conventional inhibitors.

A related class of compounds, called molecular glues, works on a similar principle but through a simpler structure. Molecular glues are small molecules that promote targeted protein degradation by stabilising interactions between E3 ubiquitin ligases and target proteins, enabling their breakdown. Unlike bifunctional PROTACs, they lack a linker and directly enhance weak protein-protein interactions. Their small size enables high cell permeability and oral bioavailability. The thalidomide derivatives that have been used in multiple myeloma for years, including lenalidomide and pomalidomide, are retrospectively understood to be molecular glues, discovered by accident before the mechanism was understood.

The FDA Approval That Changed Everything

The field crossed its most significant clinical threshold on 1 May 2026, when the FDA approved vepdegestrant (Veppanu), developed by Arvinas and Pfizer, for the treatment of ESR1-mutant, oestrogen receptor-positive, HER2-negative advanced breast cancer. The approval was granted ahead of its June 2026 Prescription Drug User Fee Act target date, underscoring both the urgency of unmet need in this patient population and the growing clinical confidence in targeted protein degradation as a therapeutic modality.

Vepdegestrant is the first approved PROTAC in history. It works by degrading the oestrogen receptor, the protein that drives tumour growth in the majority of breast cancers. In patients whose tumours have acquired mutations in the ESR1 gene, which make the receptor resistant to conventional hormone therapies such as fulvestrant, degrading the receptor rather than merely blocking it offers a meaningful clinical advantage. The oral formulation also removes the need for the monthly injections required by current standard-of-care treatments.

Beyond breast cancer, PROTAC-based approaches are being explored across a range of therapeutic areas, including neurodegenerative and neuromuscular diseases, reflecting the versatility of the platform. Arvinas has a second PROTAC in clinical development targeting LRRK2, a protein implicated in Parkinson’s disease, with the molecule specifically engineered to penetrate the blood-brain barrier.

A Week of Milestones at ASCO

The approval arrived alongside equally striking clinical data from a different branch of the degrader family. Bristol Myers Squibb presented results from the Phase 3 SUCCESSOR-2 trial at the ASCO Annual Meeting this week, evaluating mezigdomide in patients with relapsed or refractory multiple myeloma who had already received both an anti-CD38 antibody and lenalidomide, the current standard treatment.

The MeziKd combination of mezigdomide, carfilzomib and dexamethasone significantly reduced the risk of progression or death by 52% compared with carfilzomib and dexamethasone alone, with a median progression-free survival of 18.0 months versus 8.3 months. Response rates were also substantially higher, with 80.2% of patients responding to the three-drug combination compared with 53.4% in the control arm.

“In this setting, we can reasonably conclude that oral mezigdomide combined with weekly intravenous carfilzomib is a potential new standard of care in relapsed or refractory disease,” said Dr Paul G. Richardson of Dana-Farber Cancer Institute, who presented the study at ASCO.

Mezigdomide belongs to a class called CELMoDs, cereblon E3 ligase modulators, which represent a more potent and specifically engineered evolution of the older thalidomide-derived drugs. Mezigdomide is optimised for maximal and rapid degradation of the Ikaros and Aiolos target proteins, leading to higher multiple myeloma cell killing. It is one of two CELMoDs that Bristol Myers has submitted to regulators, alongside iberdomide, as intended successors to Revlimid and Pomalyst, two older myeloma drugs from the same mechanistic lineage that together generated tens of billions of dollars in revenue before patent expiry.

A Platform, Not Just a Drug

What makes targeted protein degradation commercially and scientifically significant is that it is a platform technology rather than a single therapeutic approach. The same fundamental mechanism can in principle be applied to almost any protein for which a suitable binding ligand can be found, provided a relevant E3 ligase can be recruited in proximity.

2026 marks a quarter-century of the PROTAC field, progressing from a transformative innovation to the cusp of clinical application. Within the broader field of induced-proximity pharmacology, molecular glue degraders are progressing steadily alongside the more mature but still actively expanding PROTAC technology.

Analysis of the clinical pipeline reveals three emerging trends: a shift towards oral bioavailability, the expansion into non-oncological areas such as inflammatory diseases, and a focus on overcoming resistance to established therapies. The last of these is particularly significant. One of the most persistent challenges in cancer treatment is the emergence of resistance mutations, in which tumour cells evolve to work around a drug that blocks a single site. A degrader that eliminates the entire protein, including mutated variants, offers a fundamentally different resistance profile.

The challenges that remain are real. PROTAC molecules are large and complex, raising questions about oral bioavailability and tissue penetration that early-generation compounds struggled to resolve. Manufacturing degraders at scale is more demanding than producing conventional small molecules. And the relationship between dose, degradation kinetics and clinical effect is more complicated than that seen with simple inhibitors, making dosing optimisation a genuine scientific problem.

These are engineering challenges rather than conceptual dead ends, and the field is making progress on all of them. The approval of vepdegestrant and the SUCCESSOR-2 data from this week’s ASCO meeting represent the clinical proof that the mechanism works where it matters most: in patients with serious disease and limited options. The question now is how broadly and how rapidly this platform can be applied across the full scope of diseases in which undruggable proteins play a role.

The answer, judging by the pace of investment, clinical development and regulatory confidence in 2026, is faster than most of the field expected.

Sources include Bristol Myers Squibb, Arvinas, the American Society of Clinical Oncology, CancerNetwork, BioPharm International, Frontiers in Pharmacology, BioPharma Dive and the US Food and Drug Administration.