PDBsum entry 5a85

Hydrolase

PDB id: 5a85

Contents

Protein chain

126 a.a.

Ligands

EDO

78J

Waters ×232

PDB id:

5a85

Name:

Hydrolase

Title:

N-terminal bromodomain of human brd4 with 8-(3r,4r)-3- (cyclohexylmethoxy)piperidin-4-ylamino-3-methyl-1,2-dihydro-1,7- naphthyridin-2-one

Structure:

Bromodomain-containing protein 4. Chain: a. Fragment: n-terminal bromodomain, residues 44-168. Synonym: protein hunk1, brd4. Engineered: yes

Source:

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

Resolution:

1.72Å R-factor: 0.188 R-free: 0.236

Authors:

C.Chung,P.Bamborough,E.Demont

Key ref:

P.Bamborough et al. (2015). Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors. J Med Chem, 58, 6151-6178. PubMed id: 26230603 DOI: 10.1021/acs.jmedchem.5b00773

Date:

11-Jul-15 Release date: 12-Aug-15

Protein chain

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/acs.jmedchem.5b00773

J Med Chem 58:6151-6178 (2015)

PubMed id: 26230603

Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors.

P.Bamborough, C.W.Chung, R.C.Furze, P.Grandi, A.M.Michon, R.J.Sheppard, H.Barnett, H.Diallo, D.P.Dixon, C.Douault, E.J.Jones, B.Karamshi, D.J.Mitchell, R.K.Prinjha, C.Rau, R.J.Watson, T.Werner, E.H.Demont.

ABSTRACT

ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.