7UTY

First bromodomain of BRD4 liganded with compound 2c

Summary for 7UTY

• Entry DOI: 10.2210/pdb7uty/pdb
• Descriptor: Bromodomain-containing protein 4, prop-2-en-1-yl (5S)-1-ethyl-7-methyl-5-(4-methylphenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine-6-carboxylate, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: inhibitor, acetyl-lysine, transcription regulation, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 15604.94

Authors

Schonbrunn, E.,Chan, A. (deposition date: 2022-04-28, release date: 2022-08-24, Last modification date: 2023-10-18)

Primary citation

Jiang, J.,Zhao, P.L.,Sigua, L.H.,Chan, A.,Schonbrunn, E.,Qi, J.,Georg, G.I.
1,4-Dihydropyridinebutyrolactone-derived ring-opened ester and amide analogs targeting BET bromodomains.
Arch Pharm, 355:e2200288-e2200288, 2022

PubMed Abstract: Based on a previously reported 1,4-dihydropyridinebutyrolactone virtual screening hit, nine lactone ring-opened ester and seven amide analogs were prepared. The analogs were designed to provide interactions with residues at the entrance of the ZA loop of the testis-specific bromodomain (ZA) channel to enhance the affinity and selectivity for the bromodomain and extra-terminal (BET) subfamily of bromodomains. Compound testing by AlphaScreen showed that neither the affinity nor the selectivity of the ester and lactam analogs was improved for BRD4-1 and the first bromodomain of the testis-specific bromodomain (BRDT-1). The esters retained affinity comparable to the parent compound, whereas the affinity for the amide analogs was reduced 10-fold. A representative benzyl ester analog was found to retain high selectivity for BET bromodomains as shown by a BROMOscan. X-ray analysis of the allyl ester analog in complex with BRD4-1 and BRDT-1 revealed that the ester side chain is located next to the ZA loop and solvent exposed.

PubMed: 35941525
DOI: 10.1002/ardp.202200288

Experimental method

X-RAY DIFFRACTION (1.55 Å)