PDBsum entry 4hxr

Protein binding/inhibitor

PDB id: 4hxr

Contents

Protein chain

125 a.a.

Ligands

1A4

Waters ×135

PDB id:

4hxr

Name:

Protein binding/inhibitor

Title:

Brd4 bromodomain 1 complex with n-[3-(2-oxo-2,3-dihydro-1,3-thiazol-4- yl)phenyl]thiophene-2-sulfonamide inhibitor

Structure:

Bromodomain-containing protein 4. Chain: a. Synonym: protein hunk1. Engineered: yes

Source:

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

Resolution:

1.53Å R-factor: 0.174 R-free: 0.199

Authors:

T.T.Chen,D.Y.Cao,W.Y.Chen,B.Xiong,J.K.Shen,Y.C.Xu

Key ref:

L.Zhao et al. (2013). Fragment-based drug discovery of 2-thiazolidinones as inhibitors of the histone reader BRD4 bromodomain. J Med Chem, 56, 3833-3851. PubMed id: 23530754 DOI: 10.1021/jm301793a

Date:

12-Nov-12 Release date: 03-Apr-13

Protein chain

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

Seq: 1362 a.a.

Struc: 125 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/jm301793a

J Med Chem 56:3833-3851 (2013)

PubMed id: 23530754

Fragment-based drug discovery of 2-thiazolidinones as inhibitors of the histone reader BRD4 bromodomain.

L.Zhao, D.Cao, T.Chen, Y.Wang, Z.Miao, Y.Xu, W.Chen, X.Wang, Y.Li, Z.Du, B.Xiong, J.Li, C.Xu, N.Zhang, J.He, J.Shen.

ABSTRACT

Recognizing acetyllysine of histone is a vital process of epigenetic regulation that is mediated by a protein module called bromodomain. To contribute novel scaffolds for developing into bromodomain inhibitors, we utilize a fragment-based drug discovery approach. By successively applying docking and X-ray crystallography, we were able to identify 9 fragment hits from diffracting more than 60 crystals. In the present work, we described four of them and carried out the integrated lead optimization for fragment 8, which bears a 2-thiazolidinone core. After several rounds of structure guided modifications, we assessed the druggability of 2-thiazolidinone by modulating in vitro pharmacokinetic studies and cellular activity assay. The results showed that two potent compounds of 2-thiazolidinones have good metabolic stability. Also, the cellular assay confirmed the activities of 2-thiazolidinones. Together, we hope the identified 2-thiazolidinone chemotype and other fragment hits described herein can stimulate researchers to develop more diversified bromodomain inhibitors.