PDBsum entry 4z1s

Signaling protein

PDB id: 4z1s

Contents

Protein chains

126 a.a.

Ligands

559 ×2

Waters ×308

PDB id:

4z1s

Name:

Signaling protein

Title:

Crystal structure of the first bromodomain of human brd4 with benzotriazolo-diazepine scaffold

Structure:

Bromodomain-containing protein 4. Chain: a, b. Fragment: unp residues 42-166. Synonym: protein hunk1. Engineered: yes

Source:

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

Resolution:

1.06Å R-factor: 0.187 R-free: 0.220

Authors:

J.W.Setser,F.Poy,Y.Tang,S.F.Bellon

Key ref:

A.M.Taylor et al. (2016). Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains. Acs Med Chem Lett, 7, 145-150. PubMed id: 26985289 DOI: 10.1021/ml500411h

Date:

27-Mar-15 Release date: 08-Apr-15

Protein chains

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

Seq: 1362 a.a.

Struc: 126 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/ml500411h

Acs Med Chem Lett 7:145-150 (2016)

PubMed id: 26985289

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.

A.M.Taylor, R.G.Vaswani, V.S.Gehling, M.C.Hewitt, Y.Leblanc, J.E.Audia, S.Bellon, R.T.Cummings, A.Côté, J.C.Harmange, H.Jayaram, S.Joshi, J.M.Lora, J.A.Mertz, A.Neiss, E.Pardo, C.G.Nasveschuk, F.Poy, P.Sandy, J.W.Setser, R.J.Sims, Y.Tang, B.K.Albrecht.

ABSTRACT

Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.