| Structural highlights
Disease
[BRD4_HUMAN] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.[1] [2]
Function
[BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
Publication Abstract from PubMed
Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology.
Naphthyridines as Novel BET Family Bromodomain Inhibitors.,Mirguet O, Lamotte Y, Chung CW, Bamborough P, Delannee D, Bouillot A, Gellibert F, Krysa G, Lewis A, Witherington J, Huet P, Dudit Y, Trottet L, Nicodeme E ChemMedChem. 2013 Sep 2. doi: 10.1002/cmdc.201300259. PMID:24000170[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
- ↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
- ↑ Mirguet O, Lamotte Y, Chung CW, Bamborough P, Delannee D, Bouillot A, Gellibert F, Krysa G, Lewis A, Witherington J, Huet P, Dudit Y, Trottet L, Nicodeme E. Naphthyridines as Novel BET Family Bromodomain Inhibitors. ChemMedChem. 2013 Sep 2. doi: 10.1002/cmdc.201300259. PMID:24000170 doi:10.1002/cmdc.201300259
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