Massive barcode-free chemical screenings enable the discovery of bioactive macrocycles with passive membrane permeability - PubMed
8 hours ago
- #high-throughput screening
- #drug discovery
- #macrocycles
- CycloSEL is a new workflow for screening synthetic macrocycle libraries without genetic barcodes, using affinity selections and tandem mass spectrometry.
- It was validated with a 16 million-member library against carbonic anhydrase IX, showing robust enrichment and accurate binder identification.
- Applied to the WDR5 target, it yielded a subnanomolar affinity macrocycle that inhibits the WDR5-MLL1 interaction.
- Modified macrocycles demonstrated passive membrane permeability, serum stability, and anti-proliferative activity in leukemia cells.
- The approach enables discovery of drug-like macrocycles for intracellular targets from fully synthetic libraries.