2015
DOI: 10.1021/ml500411h
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Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

Abstract: Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo [b]isoxazolo [4,5-d] T he bromodomain and extra terminal (BET) family is made up of BRD2, BRD3, BRD4, and BRDT, each of which contains tandem bromodomains (BD-1 and BD-2) that recognize specific acetylated lysine residues in the N-terminal tails of… Show more

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Cited by 29 publications
(28 citation statements)
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“…These findings were consistent with previous observations that the relatively large and hydrophobic acetyl‐lysine binding pockets of BET bromodomains are highly druggable compared to other bromodomains . Indeed, many screening efforts have successfully identified small molecules for BET bromodomain acetyl‐lysine binding pockets . In summary, screening BRD4(BD2) against our chemical library identified acetaminophen, a compound known to interact with bromodomains, and demonstrated the feasibility and success of our approach in identifying compounds that interact with target proteins for further characterization.…”
Section: Resultssupporting
confidence: 91%
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“…These findings were consistent with previous observations that the relatively large and hydrophobic acetyl‐lysine binding pockets of BET bromodomains are highly druggable compared to other bromodomains . Indeed, many screening efforts have successfully identified small molecules for BET bromodomain acetyl‐lysine binding pockets . In summary, screening BRD4(BD2) against our chemical library identified acetaminophen, a compound known to interact with bromodomains, and demonstrated the feasibility and success of our approach in identifying compounds that interact with target proteins for further characterization.…”
Section: Resultssupporting
confidence: 91%
“…Baseplane noise was not shown to contributes ignificantly to DIA values( Figures S2 and S4). Manual inspection of spectral overlays for these ten samples verified that the seven samples with the highest positivei ntensityv alues (1,24,31,39,40,45, and 50) derived from distinct CSPs. By contrast, the three samples with the lowestp ositive intensity values above the + +1 s threshold (23, 53, and 54) did not give rise to substantial CSPs and were classified as false positives.…”
Section: Resultsmentioning
confidence: 89%
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