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 μM. 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 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 toward cancer therapeutics,
further investigation of DCAF1 functions in cells, and the development
of DCAF1-based PROTACs.