6WGX

Cocrystal of BRD4(D1) with a selective inhibitor

Summary for 6WGX

• Entry DOI: 10.2210/pdb6wgx/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 4-(1-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-4-[4-(trifluoromethyl)phenyl]-1H-imidazol-5-yl)-N-(3,5-dimethylphenyl)pyrimidin-2-amine, ... (4 entities in total)
• Functional Keywords: brd4, gene regulation, gene regulation-inhibitor complex, gene regulation/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 31636.42

Authors

Johnson, J.A.,Cui, H.,Shi, K.,Aihara, H.,Pomerantz, W.C.K. (deposition date: 2020-04-06, release date: 2020-10-07, Last modification date: 2023-10-18)

Primary citation

Cui, H.,Divakaran, A.,Pandey, A.K.,Johnson, J.A.,Zahid, H.,Hoell, Z.J.,Ellingson, M.O.,Shi, K.,Aihara, H.,Harki, D.A.,Pomerantz, W.C.K.
Selective N-Terminal BET Bromodomain Inhibitors by Targeting Non-Conserved Residues and Structured Water Displacement*.
Angew.Chem.Int.Ed.Engl., 60:1220-1226, 2021

PubMed Abstract: Bromodomain and extra-terminal (BET) family proteins, BRD2-4 and T, are important drug targets; however, the biological functions of each bromodomain remain ill-defined. Chemical probes that selectively inhibit a single BET bromodomain are lacking, although pan inhibitors of the first (D1), and second (D2), bromodomain are known. Here, we develop selective BET D1 inhibitors with preferred binding to BRD4 D1. In competitive inhibition assays, we show that our lead compound is 9-33 fold selective for BRD4 D1 over the other BET bromodomains. X-ray crystallography supports a role for the selectivity based on reorganization of a non-conserved lysine and displacement of an additional structured water in the BRD4 D1 binding site relative to our prior lead. Whereas pan-D1 inhibitors displace BRD4 from MYC enhancers, BRD4 D1 inhibition in MM.1S cells is insufficient for stopping Myc expression and may lead to its upregulation. Future analysis of BRD4 D1 gene regulation may shed light on differential BET bromodomain functions.

PubMed: 32975004
DOI: 10.1002/anie.202008625

Experimental method

X-RAY DIFFRACTION (1.53 Å)