Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family

Filippakopoulos, P.; Picaud, S.; Fedorov, O.; Keller, Marco; Wrobel, Matthias N.; Morgenstern, Olaf; Bracher, Franz; Knapp, Stefan

doi:10.1016/j.bmc.2011.10.080

Cited by 112 publications

(116 citation statements)

References 38 publications

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“…50 Notably, the widely prescribed anxiolytic alprazolam (21) bound to BRD4(1) with a K D of 2.5 μM [cf. 0.05 μM for (+)-2] ( Figure 8A,B); however, the authors note that this affinity means that it is unlikely that alprazolam has any effect on bromodomains at clinically relevant doses.…”

Section: Family Of Bromodomainsmentioning

confidence: 99%

Progress in the Development and Application of Small Molecule Inhibitors of Bromodomain–Acetyl-lysine Interactions

et al. 2012

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Bromodomains, protein modules that recognize and bind to acetylated lysine, are emerging as important components of cellular machinery. These acetyl-lysine (KAc) "reader" domains are part of the write-read-erase concept that has been linked with the transfer of epigenetic information. By reading KAc marks on histones, bromodomains mediate protein-protein interactions between a diverse array of partners. There has been intense activity in developing potent and selective small molecule probes that disrupt the interaction between a given bromodomain and KAc. Rapid success has been achieved with the BET family of bromodomains, and a number of potent and selective probes have been reported. These compounds have enabled linking of the BET bromodomains with diseases, including cancer and inflammation, suggesting that bromodomains are druggable targets. Herein, we review the biology of the bromodomains and discuss the SAR for the existing small molecule probes. The biology that has been enabled by these compounds is summarized.

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Section: Family Of Bromodomainsmentioning

confidence: 99%

Progress in the Development and Application of Small Molecule Inhibitors of Bromodomain–Acetyl-lysine Interactions

et al. 2012

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“…We found that benzo-diazepine and benzo-triazepine scaffolds exhibit affinity for BET BRDs providing good starting points for rational inhibitor design [99]. We developed a cell-permeable and potent inhibitor (JQ1), based on a triazolo-thieno-diazepine scaffold with high affinity and selectivity for all BET BRDs [19].…”

Section: Inhibition Of Brd-specific K Ac Readoutmentioning

confidence: 99%

The bromodomain interaction module

2012

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a b s t r a c t e-N-acetylation of lysine residues (K ac ) is one of the most abundant post-translation modifications (PTMs) in the human proteome. In the nucleus, acetylation of histones has been linked to transcriptional activation of genes but the functional consequences of most acetylation events and proteins recruited to these sites remains largely unknown. Bromodomains (BRDs) are small helical interaction modules that specifically recognize acetylation sites in proteins. BRDs have recently emerged as interesting targets for the development of specific protein interaction inhibitors, enabling a novel exiting strategy for the development of new therapies. This review provides an overview over sequence requirements of BRDs, known substrates and the structural mechanisms of specific K ac recognition.

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“…A striking example of the effect of JQ1 is its ability to control male fertility via reversible inhibition of the testis-specific protein BRDT in mice [54]. Notably, some drugs currently on the market can also bind bromodomains, as recently demonstrated for alprazolam and midazolam [55], but the importance of these interactions in their therapeutic effects is unknown.…”

Section: Epidrugsmentioning

confidence: 96%

Epigenetic mechanisms of importance for drug treatment

Ivanov¹,

Barragán²,

Ingelman‐Sundberg

2014

Trends in Pharmacological Sciences

133

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Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family

Abstract: Graphical abstractA number of triazolo-benzodiazepines including drugs such as alprazolam have been developed as protein interaction inhibitors that target bromodomains of the BET family.

Cited by 112 publications

References 38 publications

Progress in the Development and Application of Small Molecule Inhibitors of Bromodomain–Acetyl-lysine Interactions

Progress in the Development and Application of Small Molecule Inhibitors of Bromodomain–Acetyl-lysine Interactions

The bromodomain interaction module

Epigenetic mechanisms of importance for drug treatment

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