PDBsum entry 4yh4

Protein binding

PDB id: 4yh4

Contents

Protein chain

127 a.a.

Ligands

Y81

GOL

Metals

_NA

Waters ×249

PDB id:

4yh4

Name:

Protein binding

Title:

Crystal structure of human brd4(1) in complex with 4-[(5- phenylpyridin-3-yl)carbonyl]-3,4-dihydroquinoxalin-2(1h)-one (compound 19d)

Structure:

Bromodomain-containing protein 4. Chain: a. Fragment: bromodomain 1 (unp residues 44-170). Synonym: protein hunk1, brd4. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brd4, hunk1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.33Å R-factor: 0.109 R-free: 0.147

Authors:

D.Lakshminarasimhan,A.White,R.K.Suto

Key ref:

B.C.Duffy et al. (2015). Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design. Bioorg Med Chem Lett, 25, 2818-2823. PubMed id: 26022843 DOI: 10.1016/j.bmcl.2015.04.107

Date:

26-Feb-15 Release date: 13-Jan-16

Protein chain

O60885  (BRD4_HUMAN) -  Bromodomain-containing protein 4 from Homo sapiens

Seq: 1362 a.a.

Struc: 127 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1016/j.bmcl.2015.04.107

Bioorg Med Chem Lett 25:2818-2823 (2015)

PubMed id: 26022843

Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.

B.C.Duffy, S.Liu, G.S.Martin, R.Wang, M.M.Hsia, H.Zhao, C.Guo, M.Ellis, J.F.Quinn, O.A.Kharenko, K.Norek, E.M.Gesner, P.R.Young, K.G.McLure, G.S.Wagner, D.Lakshminarasimhan, A.White, R.K.Suto, H.C.Hansen, D.B.Kitchen.

ABSTRACT

Bromodomains are key transcriptional regulators that are thought to be druggable epigenetic targets for cancer, inflammation, diabetes and cardiovascular therapeutics. Of particular importance is the first of two bromodomains in bromodomain containing 4 protein (BRD4(1)). Protein-ligand docking in BRD4(1) was used to purchase a small, focused screening set of compounds possessing a large variety of core structures. Within this set, a small number of weak hits each contained a dihydroquinoxalinone ring system. We purchased other analogs with this ring system and further validated the new hit series and obtained improvement in binding inhibition. Limited exploration by new analog synthesis showed that the binding inhibition in a FRET assay could be improved to the low μM level making this new core a potential hit-to-lead series. Additionally, the predicted geometries of the initial hit and an improved analog were confirmed by X-ray co-crystallography with BRD4(1).