8EWV

DNA-encoded library (DEL)-enabled discovery of proximity inducing small molecules

Summary for 8EWV

• Entry DOI: 10.2210/pdb8ewv/pdb
• Descriptor: Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (5 entities in total)
• Functional Keywords: molecular glue, bifunctional compound, brd4, vcb, dna-encoded libraries, apoptosis
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 24
• Total formula weight: 352458.72

Authors

Schreiber, S.L.,Shu, W.,Ma, X.,Michaud, G.,Bonazzi, S.,Berst, F. (deposition date: 2022-10-24, release date: 2023-10-04, Last modification date: 2024-02-14)

Primary citation

Mason, J.W.,Chow, Y.T.,Hudson, L.,Tutter, A.,Michaud, G.,Westphal, M.V.,Shu, W.,Ma, X.,Tan, Z.Y.,Coley, C.W.,Clemons, P.A.,Bonazzi, S.,Berst, F.,Briner, K.,Liu, S.,Zecri, F.J.,Schreiber, S.L.
DNA-encoded library-enabled discovery of proximity-inducing small molecules.
Nat.Chem.Biol., 20:170-179, 2024

PubMed Abstract: Small molecules that induce protein-protein associations represent powerful tools to modulate cell circuitry. We sought to develop a platform for the direct discovery of compounds able to induce association of any two preselected proteins, using the E3 ligase von Hippel-Lindau (VHL) and bromodomains as test systems. Leveraging the screening power of DNA-encoded libraries (DELs), we synthesized ~1 million DNA-encoded compounds that possess a VHL-targeting ligand, a variety of connectors and a diversity element generated by split-and-pool combinatorial chemistry. By screening our DEL against bromodomains in the presence and absence of VHL, we could identify VHL-bound molecules that simultaneously bind bromodomains. For highly barcode-enriched library members, ternary complex formation leading to bromodomain degradation was confirmed in cells. Furthermore, a ternary complex crystal structure was obtained for our most enriched library member with BRD4 and a VHL complex. Our work provides a foundation for adapting DEL screening to the discovery of proximity-inducing small molecules.

PubMed: 37919549
DOI: 10.1038/s41589-023-01458-4

Experimental method

X-RAY DIFFRACTION (3.4 Å)