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

Heterobifunctional proteolysis targeting chimeras (PROTACs) are proven to degrade disease-causing proteins, and many PROTACs have already entered into clinical trials. The majority of these PROTACs recruit cereblon (CRBN) or von Hippel–Lindau (VHL) substrate receptors of cullin RING E3 ubiquitin ligases, but there remains a need for alternative E3 ligase ligands. In this study, we enable DDB1 as an E3 ligase adapter protein for PROTAC drug discovery, describe a DNA-encoded library (DEL) ligand discovery campaign, and report the identification of a novel DDB1 ligand. Structure-guided modifications allowed DDB1 ligands to be developed from the initial DEL hit with nanomolar potency. Biochemical assays, cellular target engagement, and X-ray crystallography analysis demonstrated binding of the ligand to a unique pocket within DDB1. This chemical series furthers our understanding of ligand binding pockets within DDB1 and expands the repertoire of small molecules that may be suitable for the incorporation into PROTACs.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2026-03-27
DOI
https://doi.org/10.1021/acsmedchemlett.6c00003
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
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article

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

Amanda Chapman, Miklós Békés, Gabriella Miklóssy, Arman Fathizadeh et al.
ACS Medicinal Chemistry Letters
Protein Degradation and Inhibitors
article

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

Amanda Chapman, Miklós Békés, Gabriella Miklóssy, Arman Fathizadeh, John Corradi, Cory M. Stiff, Katherine M. Digianantonio, Gan Wang, Sarah Prophet, Rashaun S. Wilson, Brett R. Beno, David R. Langley, Peter C. Gareiss, Avani Patel, Alicia Harbin, Hanqing Dong, Shiva Krishna Reddy Guduru, John P. Caldwell, Christine Jones, Kurt Zimmermann (327735), Brittany Driscoll, Antonella P. Stroppa, Nicholas T. Barczak, Marci Crandall, Alexander Scott, Md Fazlul Karim, Lin Yuan, Angela M. Cacace, Natalie RG. Reinhardt, Song Yang, Jordan J. Clark, Mee-Kyung Chung, William E. Butcher
article en

Abstract

Heterobifunctional proteolysis targeting chimeras (PROTACs) are proven to degrade disease-causing proteins, and many PROTACs have already entered into clinical trials. The majority of these PROTACs recruit cereblon (CRBN) or von Hippel–Lindau (VHL) substrate receptors of cullin RING E3 ubiquitin ligases, but there remains a need for alternative E3 ligase ligands. In this study, we enable DDB1 as an E3 ligase adapter protein for PROTAC drug discovery, describe a DNA-encoded library (DEL) ligand discovery campaign, and report the identification of a novel DDB1 ligand. Structure-guided modifications allowed DDB1 ligands to be developed from the initial DEL hit with nanomolar potency. Biochemical assays, cellular target engagement, and X-ray crystallography analysis demonstrated binding of the ligand to a unique pocket within DDB1. This chemical series furthers our understanding of ligand binding pockets within DDB1 and expands the repertoire of small molecules that may be suitable for the incorporation into PROTACs.

ACS Medicinal Chemistry Letters
Arvinas (United States) (US)
Good health and well-being
Openalex Percentile: Top 4%
Protein Degradation and Inhibitors
DOISourceOpenAlex
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