DNA-Encoded Library (DEL) Selection Identifies a Distinct DDB1 Ligand Binding Site

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• Proteolysis targeting chimeras (PROTACs) are an emerging therapeutic modality for targeted protein degradation.
• Current PROTACs predominantly utilize cereblon (CRBN) or von Hippel-Lindau (VHL) E3 ligase ligands.
• There is a significant need for novel E3 ligase ligands to expand the scope of PROTAC technology.

Purpose of the Study:

• To establish DDB1 as a viable E3 ligase adapter for PROTAC development.
• To identify novel DDB1 ligands using a DNA-encoded library (DEL) approach.
• To optimize initial DEL hits into potent DDB1 ligands.

Main Methods:

• DNA-encoded library (DEL) screening for DDB1 ligand discovery.
• Structure-guided medicinal chemistry for ligand optimization.
• Biochemical assays, cellular target engagement studies, and X-ray crystallography for characterization.

Main Results:

• Identification of a novel DDB1 ligand from a DEL campaign.
• Optimization of DEL hits to achieve nanomolar potency.
• Demonstration of ligand binding to a unique pocket in DDB1 via structural and biochemical analyses.

Conclusions:

• DDB1 can be effectively utilized as an E3 ligase adapter for PROTAC drug discovery.
• The identified DDB1 ligands represent a new chemical series with therapeutic potential.
• This work expands the toolbox of small molecules for PROTAC development, offering alternatives to CRBN and VHL ligands.