Discovery of Nanomolar DCAF1 Small Molecule Ligands
DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used towards the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of compound (Z1391232269) with a SPR KD of 11 µM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with SPR KD of 38 nM and cellular target engagement with EC50 of 10 µM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next generation DCAF1 ligands towards cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.