Most degrader discovery programs start with a hypothesis: pick the target, pick the E3 ligase, pick a binding pocket, then screen for a molecule that connects them. Matthias Brand, cofounder and Chief Technology Officer of Proxygen, told DDN that approach can cause programs to miss their best candidates before they're found.
Molecular glue degraders can act through a wide range of mechanisms, engaging any of the roughly 600 E3 ligases in the human genome, and sometimes without directly binding the E3 ligase or the target protein at all.
"Entering a screen with too narrow a focus risks missing the molecules that would achieve the desired end result eliminating the target simply because they operate through a different machinery than interrogated by the screen," Brand said. Since true glue degraders are intrinsically rare, he added, that narrow focus can determine whether an entire campaign succeeds or fails.
Starting from the outcome, not the mechanism
Proxygen's platform is built around what the company calls a deconvolution strategy: screening for the functional outcome, meaning the specific and selective elimination of a disease-causing protein, before identifying which mechanism produced it. Brand said this lets the company capture productive mechanisms it might otherwise design around, and take advantage of whichever cellular components are best suited to a given target. Weak baseline affinity and complementary protein surfaces between a target and a ligase, for example, can prime an interaction that the glue molecule then stabilizes.
Only after a hit is identified does Proxygen dissect the underlying mechanism, using functional genomics, chemical biology, interaction proteomics, and structural biology to characterize what is happening at the molecular level. That characterization work, Brand said, is what enables optimization toward a drug candidate and helps identify liabilities to derisk early.
Targeting proteins without a pocket
The approach is aimed partly at protein classes that have resisted conventional drug discovery. Transcription factors, scaffolding proteins, and other intrinsically disordered proteins have long been considered undruggable because they lack well-defined binding pockets, or because the pockets they have are not functionally relevant to disease. Brand said that these proteins function largely through protein-protein or protein-DNA interactions, surfaces that small molecules struggle to grip and that biologics cannot reach because they do not enter cells.
Even for targets that classical inhibitors can already modulate, Brand argued there is room for glue degraders to outperform them on selectivity. Inhibitor development often forces a trade-off between on-target coverage and off-target toxicity, since targeted pockets tend to be conserved across a protein family. Molecular glues, he said, can be substantially more selective by exploiting small differences in the protein surface outside that conserved active site, combined with a catalytic mechanism where limited protein engagement is enough to drive pronounced, prolonged degradation.
Screening scale and hit prioritization
Proxygen tailors the scale of each screen to the target's biology, Brand said, ranging from focused custom libraries of a few thousand molecules to diversity libraries exceeding a million compounds. Because many compounds can lower target protein levels without being true glue degraders — through nonspecific effects on transcription, translation, or broader cell signaling — rigorous counter-screening is central to separating real degraders from noise. Over time, the company has built a multidimensional profile, weighing degradation kinetics, structure-activity relationships, selectivity, and depth of degradation, to prioritize hits with a realistic path to optimization.
Pipeline moving toward IND-enabling studies
Proxygen's two lead programs, a highly selective p300/CBP dual degrader and a brain-penetrant CDK12 degrader, are both substantially differentiated from competitor molecules and on track to enter Investigational New Drug-enabling studies next year, according to Brand.
Brand also pointed to work beyond degradation. Induced proximity more broadly, he said, can reshape protein-protein interactions and rewire cellular signaling networks by redirecting targets to different effector proteins, work he described as opening a design space for treatments in oncology and other disease areas. Proxygen's early programs in this space, including efforts to rewire transcriptional programs or reprogram oncogenes toward cell death, are expected to generate proof-of-concept data this year.
