9ZYT

Crystal Structure of BRD4 Bromodomain BD1 in Complex with Small Molecule PLX-3618

This is a non-PDB format compatible entry.

Summary for 9ZYT

• Entry DOI: 10.2210/pdb9zyt/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, PLX-3618, ... (4 entities in total)
• Functional Keywords: brd4, bromodomain bd1, gene regulation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 31409.28

Authors

Leriche, G.,Barmare, F.,Toth, J.I.,Jamborcic, A.,Kampert, T.L.,Steadman, K.,Yang, L.,Fish, S.,Daniele, E.,McCarrick, M.,Kallel, E.A.,Li, X.,Thompson, P.A.,Parker, G.S.,Freeman-Cook, K.,Bailey, S. (deposition date: 2026-01-06, release date: 2026-04-22, Last modification date: 2026-06-03)

Primary citation

Leriche, G.,Barmare, F.,Toth, J.I.,Jamborcic, A.,Kampert, T.L.,Steadman, K.,Yang, L.,Fish, S.,Daniele, E.,McCarrick, M.,Kallel, E.A.,Li, X.,Thompson, P.A.,Parker, G.S.,Freeman-Cook, K.,Bailey, S.
Discovery and Structural Optimization of BRD4-Selective Monovalent Direct Degraders.
Acs Med.Chem.Lett., 17:1106-1113, 2026

PubMed Abstract: Targeted protein degradation (TPD) via the ubiquitin-proteasome system (UPS) is a rapidly advancing drug discovery strategy that enables the selective elimination of pathogenic proteins using small molecules. Here, we report the discovery of BRD4-selective monovalent direct degraders acting through DCAF11, identified by ultrahigh-throughput screening and subsequently optimized through a structure-guided medicinal chemistry campaign. Structure-activity relationship (SAR) studies support a direct degrader mechanism and culminated in the identification of the orally bioavailable compound . In vitro, induces rapid, complete, and selective degradation of BRD4 and exhibits potent antiproliferative activity in acute myeloid leukemia (AML) models. In vivo, treatment resulted in complete tumor regression in the AML MV-4-11 xenograft model. Collectively, this lays the groundwork for the rational development of monovalent direct degraders with applications extending beyond BRD4.

PubMed: 42157816
DOI: 10.1021/acsmedchemlett.6c00022

Experimental method

X-RAY DIFFRACTION (1.661 Å)