Discovery of Nanomolar DCAF1 Small Molecule Ligands.

ABSTRACT: DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4^DCAF1 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 K_D of 11 μM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR K_D of 38 nM and cellular target engagement with EC₅₀ of 10 μM as measured by cellular thermal shif

SUBMITTER: Li ASM 

PROVIDER: S-EPMC10108359 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature