PDBsum entry 6sa3

Transcription

PDB id: 6sa3

Contents

Protein chain

109 a.a.

Ligands

L2N

Waters ×76

PDB id:

6sa3

Name:

Transcription

Title:

Crystal structure of brd4(1) bound to inhibitor bux4 (13)

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:

1.80Å R-factor: 0.195 R-free: 0.231

Authors:

M.Huegle

Key ref:

M.Hügle et al. (2020). 4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines. J Med Chem, 63, 15603-15620. PubMed id: 33275431 DOI: 10.1021/acs.jmedchem.0c00478

Date:

16-Jul-19 Release date: 09-Dec-20

Protein chain

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

Seq: 1362 a.a.

Struc: 109 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/acs.jmedchem.0c00478

J Med Chem 63:15603-15620 (2020)

PubMed id: 33275431

4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines.

M.Hügle, P.Regenass, R.Warstat, M.Hau, K.Schmidtkunz, X.Lucas, D.Wohlwend, O.Einsle, M.Jung, B.Breit, S.Günther.

ABSTRACT

Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI₅₀ determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.