Targeted Protein Degradation (TPD) Will Unlock the Undruggable Proteome — PROTAC Technology Is Just the Beginning

~80% of the human proteome is considered "undruggable" by traditional small-molecule inhibitors — no binding pocket, no enzymatic activity to block. PROTACs (proteolysis targeting chimeras) bypass this by hijacking the cell's ubiquitin-proteasome system to degrade target proteins entirely, regardless of function.

ARV-471 (Arvinas) targeting estrogen receptor in breast cancer is in Phase III. But PROTACs have limitations: high molecular weight, poor oral bioavailability, hook effect at high concentrations.

Hypothesis: Molecular glue degraders — small molecules that create new protein-protein interfaces between a target and an E3 ligase — will surpass PROTACs as the dominant TPD modality by 2030. Molecular glues are smaller (better drug-like properties), substoichiometric (catalytic), and have already produced approved drugs (thalidomide analogs). AI-driven discovery of new molecular glues will open >500 previously undruggable targets.

Prediction: By 2030, >10 molecular glue degraders will be in clinical trials, versus ~5 PROTACs, and the first non-thalidomide molecular glue will receive FDA approval.