Ugi chemistry turns ligand libraries into PROTACs for target-agnostic screening
- A one-pot Ugi multicomponent reaction joins carboxylic-acid ligands to VHL ligand–linker conjugates in a single plate step, with solid-phase clean-up before cell assays.
- A pilot library from seven diverse ligands was screened phenotypically in six cancer lines with no target chosen in advance.
- Proteomics traced the best hit, a BI2536-derived degrader, to BRD4 degradation with clear selectivity over PLK1; NanoBRET and modeling supported ternary complex formation.
- Ugi-built photoaffinity probes confirmed BRD4 as the direct binding partner.
💡 Points Based on the abstract
This flips the usual PROTAC workflow: degradation phenotype first, target second. The catch is the Ugi linker, which is stubby and amide-rich compared with optimized PROTAC linkers, so hits will likely be under-potent for many ligand classes. I'd feed it our orphan-ligand collection, then re-linker the survivors by conventional SAR.
📄 Paper · Journal of Medicinal Chemistry (ACS) ↗ Unbiased, Target-Agnostic Platform for the Synthesis and Screening of PROTAC Libraries