PDBsum entry 4z93

Transcription

PDB id: 4z93

Contents

Protein chain

112 a.a.

Ligands

4LD

EDO

Waters ×119

PDB id:

4z93

Name:

Transcription

Title:

Brd4 bromodomain 2 in complex with gamma-carboline-containing compound, number 18.

Structure:

Bromodomain-containing protein 4. Chain: a. Fragment: bromodomain 2 (unp residues 349-460). Synonym: protein hunk1. Engineered: yes

Source:

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

Resolution:

1.27Å R-factor: 0.157 R-free: 0.185

Authors:

J.L.Meagher,J.A.Stuckey

Key ref:

X.Ran et al. (2015). Structure-Based Design of γ-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors. J Med Chem, 58, 4927-4939. PubMed id: 26080064 DOI: 10.1021/acs.jmedchem.5b00613

Date:

09-Apr-15 Release date: 01-Jul-15

Protein chain

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

Seq: 1362 a.a.

Struc: 112 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1021/acs.jmedchem.5b00613

J Med Chem 58:4927-4939 (2015)

PubMed id: 26080064

Structure-Based Design of γ-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.

X.Ran, Y.Zhao, L.Liu, L.Bai, C.Y.Yang, B.Zhou, J.L.Meagher, K.Chinnaswamy, J.A.Stuckey, S.Wang.

ABSTRACT

Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of γ-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.