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 toward 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 a compound (Z1391232269) with an SPR KD of 11 mu M. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR KD of 38 nM and cellular target engagement with EC50 of 10 mu M as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.

Automated summary

DCAF1 is a substrate receptor for two E3 ligases and has critical physiological role in protein degradation, making it a potential drug target for cancer and viral treatments. By screening a large compound library and conducting hit optimization, a compound called OICR-8268 was discovered as a tool compound for the development of DCAF1 ligands for cancer therapeutics. OICR-8268 showed strong target engagement and can be used for further investigation of DCAF1 functions and the development of DCAF1-based PROTACs.