9ZXM

DDB1 delta with compound 6

This is a non-PDB format compatible entry.

Summary for 9ZXM

• Entry DOI: 10.2210/pdb9zxm/pdb
• Descriptor: DNA damage-binding protein 1, (3S,5S)-1-{(4P)-4-(2,2-difluoro-2H-1,3-benzodioxol-4-yl)-3-[(propan-2-yl)oxy]benzene-1-carbonyl}-N-methyl-5-phenylpiperidine-3-carboxamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: e3 ligase, dna-encoded library, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 96586.54

Authors

Digianantonio, K.M.,Karim, M.F.,Bekes, M. (deposition date: 2026-01-05, release date: 2026-04-08, Last modification date: 2026-04-29)

Primary citation

Reddy Guduru, S.K.,Caldwell, J.P.,Digianantonio, K.M.,Prophet, S.M.,Yang, S.,Gareiss, P.,Jones, C.,Harbin, A.,Driscoll, B.,Karim, M.F.,Scott, A.,Patel, A.,Chapman, A.E.,Crandall, M.,Miklossy, G.,Barczak, N.T.,Stroppa, A.P.,Corradi, J.P.,Clark, J.J.,Chung, M.K.,Reinhardt, N.R.,Butcher, W.E.,Wilson, R.,Stiff, C.,Fathizadeh, A.,Yuan, L.,Wang, G.,Dong, H.,Beno, B.R.,Zimmermann, K.,Langley, D.R.,Cacace, A.M.,Bekes, M.
DNA-Encoded Library (DEL) Selection Identifies a Distinct DDB1 Ligand Binding Site.
Acs Med.Chem.Lett., 17:757-767, 2026

PubMed 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.

PubMed: 41982729
DOI: 10.1021/acsmedchemlett.6c00003

Experimental method

X-RAY DIFFRACTION (2.195 Å)