PDBsum entry 5d3r

Transcription

PDB id: 5d3r

Contents

Protein chain

127 a.a.

Ligands

57C

Waters ×65

PDB id:

5d3r

Name:

Transcription

Title:

First bromodomain of brd4 bound to inhibitor xd42

Structure:

Bromodomain-containing protein 4. Chain: a. Fragment: first bromodomain, unp residues 42-168. Synonym: protein hunk1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brd4, hunk1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.20Å R-factor: 0.218 R-free: 0.243

Authors:

D.Wohlwend,M.Huegle

Key ref:

M.Hügle et al. (2016). 4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1). J Med Chem, 59, 1518-1530. PubMed id: 26731611 DOI: 10.1021/acs.jmedchem.5b01267

Date:

06-Aug-15 Release date: 20-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: 10.1021/acs.jmedchem.5b01267

J Med Chem 59:1518-1530 (2016)

PubMed id: 26731611

4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1).

M.Hügle, X.Lucas, G.Weitzel, D.Ostrovskyi, B.Breit, S.Gerhardt, O.Einsle, S.Günther, D.Wohlwend.

ABSTRACT

Several human diseases, including cancer, show altered signaling pathways resulting from changes in the activity levels of epigenetic modulators. In the past few years, small-molecule inhibitors against specific modulators, including the bromodomain and extra-terminal (BET) bromodomain family of acetylation readers, have shown early promise in the treatment of the genetically defined midline carcinoma and hematopoietic malignancies. We have recently developed a novel potent inhibitor of BET proteins, 1 (XD14[ Angew. Chem., Int. Ed. 2013 , 52 , 14055 ]), which exerts a strong inhibitory potential on the proliferation of specific leukemia cell lines. In the study presented here, we designed analogues of 1 to study the potential of substitutions on the 4-acyl pyrrole backbone to occupy additional sites within the substrate recognition site of BRD4(1). The compounds were profiled using ITC, DSF, and X-ray crystallography. We could introduce several substitutions that address previously untargeted areas of the substrate recognition site. This work may substantially contribute to the development of therapeutics with increased target specificity against BRD4-related malignancies.