| Structural highlights
Function
[BRD2_HUMAN] May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.[1]
Publication Abstract from PubMed
A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c-MYC expression. These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors.
Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors.,Sharp PP, Garnier JM, Hatfaludi T, Xu Z, Segal D, Jarman KE, Jousset H, Garnham A, Feutrill JT, Cuzzupe A, Hall P, Taylor S, Walkley CR, Tyler D, Dawson MA, Czabotar P, Wilks AF, Glaser S, Huang DCS, Burns CJ ACS Med Chem Lett. 2017 Nov 14;8(12):1298-1303. doi:, 10.1021/acsmedchemlett.7b00389. eCollection 2017 Dec 14. PMID:29259751[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ LeRoy G, Rickards B, Flint SJ. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell. 2008 Apr 11;30(1):51-60. doi: 10.1016/j.molcel.2008.01.018. PMID:18406326 doi:10.1016/j.molcel.2008.01.018
- ↑ Sharp PP, Garnier JM, Hatfaludi T, Xu Z, Segal D, Jarman KE, Jousset H, Garnham A, Feutrill JT, Cuzzupe A, Hall P, Taylor S, Walkley CR, Tyler D, Dawson MA, Czabotar P, Wilks AF, Glaser S, Huang DCS, Burns CJ. Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors. ACS Med Chem Lett. 2017 Nov 14;8(12):1298-1303. doi:, 10.1021/acsmedchemlett.7b00389. eCollection 2017 Dec 14. PMID:29259751 doi:http://dx.doi.org/10.1021/acsmedchemlett.7b00389
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