Almost every molecular glue degrader you’ve read about uses one of two E3 ligases. Cereblon or VHL.
That’s basicallyyyy it. Two tools, hundreds of programs.
The problem with relying on those two is tissue-specific expression. Cereblon expression is uneven. VHL has its own limits.
The consequence? Resistance emerges. Your drug works great in the bone marrow and falls off a cliff in tumors where the ligase isn’t expressed.
Amphista Therapeutics has been quietly building degraders that use other E3 ligases. At AACR 2026, they showed preclinical data on two programs that actually work.
Program one is a SMARCA2 degrader via DCAF16. Orally bioavailable.
Program two. TEAD degrader via FBXO22. Hits the Hippo pathway. Demonstrated in vivo tumor regression in mesothelioma models and showed synergy with osimertinib (AstraZeneca’s Tagrisso) in EGFR-mutant NSCLC preclinical models.
Also orally bioavailable – and was published as a bioRxiv preprint on the same day.
This is what the degrader field has been waiting for… a proof point that other ligases work.
Amphista Therapeutics targeted glue pipeline
AMX-883 — Acute myeloid leukemia
Small molecule · BRD9 degrader (lead clinical candidate)
SMARCA2 degrader — Oncology
Small molecule · DCAF16 molecular glue, selective vs. SMARCA4
TEAD degrader — Mesothelioma, EGFR-mutant NSCLC
Small molecule · FBXO22 molecular glue, in vivo tumor regression
Also in development: KRAS G12D, HDAC6 programs (Parkinson’s, oncology)
The degrader field is absolutely exploding right now. I feel like I see a new story everyday.
We covered the week Kymera got dual Fast Track, Gilead exercised its option, and Neomorph raised $100M.
We covered Ternary raising a seed to engineer glues with AI.
We covered TRIANA dosing the first brain-penetrant molecular glue in NSCLC.
And this week, Nurix showed CNS-penetrant BRAF and AURKA degraders at AACR.
Everyone is working cereblon. Everyone is working VHL. Amphista is showing you don’t have to.
The TEAD synergy with osimertinib is particularly interesting. EGFR-mutant NSCLC develops resistance to osimertinib through a handful of mechanisms, and TEAD reactivation via the Hippo pathway is one of them. Degrade TEAD, restore osimertinib sensitivity. On paper, that’s a second-line combination play with enormous commercial upside if it holds in humans.
Amphista has already landed collaborations with Merck Healthcare and Bristol Myers Squibb reportedly worth over $2 billion in aggregate.
Their lead clinical asset, AMX-883, is an orally delivered non-cereblon/non-VHL BRD9 degrader headed for first-in-human trials in AML in the second half of 2026.
In my opinion, that trial, once it starts, will be one of the most important degrader readouts of the year.
Keep watching this name- AMPHISTA.
The AML readout matters, but the quieter story is which big pharma writes the next check.
The Biotech Voyager
Early-stage biotech signals, personalized.
The signals that matter to you — contextualized and written directly to you — so you cut through the noise and immediately understand why it matters.
