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For years, STAT6, a key transcription factor in allergic diseases like asthma and atopic dermatitis, was considered off-limits. Traditional small molecules couldn’t get a grip on it. There were no neat pockets to bind, no enzymes to inhibit.
Yet STAT6 plays a central role in Th2-driven diseases. Activated by interleukins 4 and 13, it drives the production of IgE, fuels inflammation, and keeps chronic allergic responses alive.
Now, a new class of drugs may be flipping the scenario. Instead of trying to block STAT6, researchers are finding ways to make it disappear altogether. These molecules, called targeted protein degraders, don’t just inhibit proteins; they tag them for destruction.
The first STAT6 degrader has already entered the clinic, and it might just change how we treat allergic disease.
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PROTACs: the key to targeting STAT6
So what changed? How did STAT6 go from an undruggable target to a reasonable approach in drug development?
The turning point came with the rise of targeted protein degradation, an approach that doesn’t try to inhibit proteins but instead removes them from the cell entirely. At the heart of this strategy are PROTACs, or proteolysis-targeting chimeras. These molecules work by linking a target protein, like STAT6, to an enzyme called an E3 ubiquitin ligase. Once bound, the enzyme tags the protein for destruction, sending it off to the proteasome, basically the cell’s version of a shredder.
PROTACs don’t need to block a functional site or inhibit enzymatic activity; they just need to bind. That opens the door to degrading proteins like STAT6, which don’t offer traditional binding pockets but still play a major role in disease. It’s a subtle shift, and it’s what made STAT6 suddenly accessible to drug developers.
AK‑1690: The lab-stage trailblazer
Researchers at the University of Michigan began with a modest STAT6-binding molecule and refined it into AK‑068, a ligand with much stronger affinity and an impressive selectivity over STAT5. That foundational chemistry set the stage for designing a PROTAC: by linking AK‑068 to a cereblon-recruiting ligand, they created AK‑1690, the first highly potent and selective STAT6 degrader.
In cell-based tests, AK‑1690 was able to eliminate STAT6 at extremely low concentrations while leaving similar proteins, like STAT5, untouched even at much higher doses. This kind of precision is rare, especially when dealing with closely related targets.
What made AK‑1690 especially valuable was that scientists were able to capture the first 3D structure of STAT6 while it was bound to the drug. This molecular snapshot showed exactly how the degrader fits into its target, giving researchers a blueprint to improve its performance. With this level of detail, the team could refine the molecule to bind more tightly and break down STAT6 even more efficiently.
KT‑621: Entering the clinic
Not too long after AK-1690 set the stage, Kymera Therapeutics advanced the first oral STAT6 degrader, KT‑621, into human trials.
In a phase 1 trial completed in 2025, the drug was administered once daily and found to be well-tolerated, with no serious or severe adverse events and a safety profile similar to placebo.
Pharmacodynamic results were compelling: more than 90% STAT6 degradation in blood was achieved at low doses. At higher doses, complete degradation was observed in both blood and skin tissues, a key target in atopic dermatitis.
What sets KT‑621 apart isn’t just its potency; it’s the fact that it’s a pill. A daily oral drug that may replicate the biologic-level impact of injections could reshape how allergic diseases are treated.
Kymera began a phase 1b trial in moderate to severe atopic dermatitis in early 2025, with readouts expected in the fourth quarter of 2025. Two phase 2b studies, one in atopic dermatitis and one in asthma, are also scheduled to begin by late 2025, early 2026.
STAT6 landscape beyond KT-621
The STAT6 degrader space is rapidly evolving beyond Kymera’s clinic-first lead, with several biotechs venturing into this space, and it appears big pharma companies want in.
In June 2025, Nurix Therapeutics and Sanofi expanded their collaboration around NX‑3911, a preclinical oral STAT6 degrader. Sanofi paid $15 million upfront for the rights, with the deal carrying up to $465 million in potential milestones. Nurix has indicated that NX‑3911 is just one of several STAT6 candidates in its pipeline, suggesting broader ambitions beyond a single asset.
Gilead Sciences has also entered the STAT6 degraders space. In January 2025, it struck a major deal with LEO Pharma worth up to $1.7 billion, including $250 million upfront, to develop an oral STAT6-targeting program. The partnership includes both degraders and inhibitors, with Gilead focusing on systemic indications like asthma and atopic dermatitis, while LEO retains rights for dermatology applications.
Meanwhile, Japan’s Kaken Pharmaceuticals has licensed a STAT6 inhibitor, KP‑723, to Johnson & Johnson. Although this program targets STAT6 through inhibition rather than degradation, it reflects broader industry confidence in STAT6 as a therapeutic entry point.
STAT6 degraders: More affordable, more accessible
Oral STAT6 degraders represent a potential advantage over current injectable biologics. These small-molecule PROTACs can be manufactured at scale with lower cost, offer simpler routes of administration, and avoid the cold-chain complexity and injection burden associated with monoclonal antibodies. An oral therapy with similar efficacy could dramatically expand access and affordability in global markets.
Scientifically, these developments mark a milestone: transcription factors, long labeled “undruggable,” such as STAT6, are now not only reachable but degradable, showing efficacy in humans.
As the clinical data for KT‑621 and other candidates mature through 2025 and 2026, the biotech and medical communities will surely be watching closely.
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