Systematic Targeting of Protein Complexes with Molecular COUPLrs

Small molecules that modulate protein complexes have transformed cell biology and oncology, yet few chemical starting points exist to probe protein-protein interactions. To expand this space, we developed molecular COUPLrs, elaborated small molecules flanked by two cysteine‑reactive warheads. Using CONNECT, an integrated chemical proteomic platform that identifies proteins and complexes amenable to coupling, we revealed 171 targetable protein classes, including mutant‑selective complexes and assemblies not traditionally addressed by small molecules. We then optimized a COUPLr against the oncogenic fusion EML4‑ALK. This compound engages EML4‑ALK by binding its EML4 domain, remodeling protein dynamics, disrupting downstream signaling, and inducing proteasome‑mediated degradation of the fusion. Finally, we show that FDA‑approved drugs can be converted into COUPLrs to degrade their targets, indicating that this modality can endow existing therapeutics with new functional properties. Overall, molecular COUPLrs offer an unbiased framework to discover, characterize, and pharmacologically exploit protein complexes.