7WL4

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor SLP-50

Summary for 7WL4

• Entry DOI: 10.2210/pdb7wl4/pdb
• Descriptor: Bromodomain-containing protein 4, ~{N}-[2-ethyl-6-(4-methylpiperazin-1-yl)-3-oxidanylidene-2,7-diazatricyclo[6.3.1.0^{4,12}]dodeca-1(12),4,6,8,10-pentaen-9-yl]-2,4-bis(fluoranyl)benzenesulfonamide (3 entities in total)
• Functional Keywords: bromodomain, brd4(1), inhibitor, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 69019.39

Authors

Zhang, C.,Wang, C.,Li, W.,Zhang, Y.,Xu, Y.,Sun, L. (deposition date: 2022-01-12, release date: 2022-08-10, Last modification date: 2023-11-29)

Primary citation

Li, W.,Zhang, C.,Zhang, H.E.,Dong, R.,Liu, J.Y.,Wang, C.M.,Wang, M.,Wang, Y.W.,Wang, C.,Zhang, Y.,Shi, L.,Xu, Y.,Sun, L.P.
Design, synthesis, and anticancer evaluation of ammosamide B with pyrroloquinoline derivatives as novel BRD4 inhibitors.
Bioorg.Chem., 127:105917-105917, 2022

PubMed Abstract: Bromodomain-containing protein 4 (BRD4), which is a member of the bromodomain and extra-terminal domain (BET) family, plays an important role in the regulation of gene expression as the "reader" of epigenetic regulation. BRD4 has become a promising target to treat cancer, because the up-regulation of BRD4 expression is closely associated with the occurrence and development of various cancers. At present, several BRD4 inhibitors are in clinical trials for cancer therapy, but no BRD4 inhibitors are on the market. Here, we designed and synthesized a series of compounds bearing pyrrolo[4,3,2-de]quinolin-2(1H)-one scaffold through structural modification of natural products ammosamide B, which is a natural pyrroloquinoline derivative reported for its potential antitumor activity. All target compounds were evaluated for their BRD4 BD1 inhibition activities via the protein thermal shift assays or AlphaSceen assay. The representative compound 49 showed potent activity (IC = 120 nM). The co-crystal of compound 49 with BRD4 BD1 was solved to study the structure activity relationship, which showed that 49 could combine with the acetyl lysine binding site and formed a hydrogen bond with the conserved residue Asn140. The results demonstrate that compound 49 is worthy of further investigation as a promising BRD4 inhibitor.

PubMed: 35738217
DOI: 10.1016/j.bioorg.2022.105917

Experimental method

X-RAY DIFFRACTION (1.82 Å)