PDBsum entry 4uyf

Transcription

PDB id: 4uyf

Contents

Protein chains

119 a.a.

108 a.a.

Ligands

EDO ×3

73B ×3

SO4 ×3

Waters ×388

PDB id:

4uyf

Name:

Transcription

Title:

N-terminal bromodomain of human brd2 with i-bet726 (gsk1324726a)

Structure:

Bromodomain-containing protein 2. Chain: a. Fragment: n-terminal bromodomain, unp residues 67-200. Synonym: o27.1.1, really interesting new gene 3 protein, human brd2. Engineered: yes. Bromodomain-containing protein 2. Chain: b, c. Fragment: n-terminal bromodomain, unp residues 67-200. Synonym: o27.1.1, really interesting new gene 3 protein, human brd2.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

1.60Å R-factor: 0.181 R-free: 0.207

Authors:

C.Chung,P.Bamborough,R.Gosmini

Key ref:

R.Gosmini et al. (2014). The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor. J Med Chem, 57, 8111-8131. PubMed id: 25249180 DOI: 10.1021/jm5010539

Date:

31-Aug-14 Release date: 08-Oct-14

Protein chain

P25440  (BRD2_HUMAN) -  Bromodomain-containing protein 2 from Homo sapiens

Seq: 801 a.a.

Struc: 119 a.a.*

Protein chains

P25440  (BRD2_HUMAN) -  Bromodomain-containing protein 2 from Homo sapiens

Seq: 801 a.a.

Struc: 108 a.a.

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

Enzyme reactions

• Enzyme class: Chains A, B, C: E.C.?

DOI no: 10.1021/jm5010539

J Med Chem 57:8111-8131 (2014)

PubMed id: 25249180

The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor.

R.Gosmini, V.L.Nguyen, J.Toum, C.Simon, J.M.Brusq, G.Krysa, O.Mirguet, A.M.Riou-Eymard, E.V.Boursier, L.Trottet, P.Bamborough, H.Clark, C.W.Chung, L.Cutler, E.H.Demont, R.Kaur, A.J.Lewis, M.B.Schilling, P.E.Soden, S.Taylor, A.L.Walker, M.D.Walker, R.K.Prinjha, E.Nicodème.

ABSTRACT

Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.