In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).

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The identification of a novel series of small molecule BET inhibitors is described. Using crystallographic binding modes of an amino-isoxazole fragment and known BET inhibitors, a structure-based drug design effort lead to a novel isoxazole azepine scaffold. This scaffold showed good potency in biochemical and cellular assays and oral activity in an in vivo model of BET inhibition.

This evaluative study assessed the feasibility and outcome of delivering speech-language services from a distance to children and adolescents who stutter. All six patients who formed the first cohort seen in the telespeech programme were included in the study. The results demonstrated that interactive videoconferencing can provide a feasible and effective care delivery model. Patient attendance was maintained throughout the intervention. All participants showed improved fluency. Stuttering ranged from 13% to 36% before treatment and 2% to 26% after treatment. All participants maintained at least part of their improved fluency during the six-month follow-up, when stuttering ranged from 4% to 32%. The study demonstrates that full assessment and treatment of stuttering in children and adolescents can be accomplished successfully via telemedicine.

CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzo [b][1,4]diazepin-2-one.

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The asymmetric synthesis of L-699,392 (1) [3-[[(1S)-[3(E)-[2-(7-chloroquinolinyl)ethenyllphenyll-3-(acetylphenyl)propyl]thio]-2(S)-methylpropanoic acid], a leukotriene antagonist, is accomplished in six steps starting from the monoaldehyde 2. The main framework of the molecule is formed via a Pd-catalyzed Heck reaction. The asymmetric center is introduced via the chiral reduction of the ketone 4 using optically active B-chlorodiisopinocampheylborane (10) derived directly from chloroborane and (-)-a-pinene. A very high asymmetric amplification is observed in which 95% ee product can be obtained from 70% optically pure a-pinene. Reagent 17, which is prepared in situ from methylmagnesium chloride and 2 equiv of lithium hexamethyldisilazide, is used to convert the methyl ester 5 to the methyl ketone 6 in one step with essentially no impurities formed under the reaction conditions. The thio side chain is finally incorporated by the displacement of the chiral mesylate 7 with complete inversion at the chiral center. The overall yield for the sequence is 42 7%.

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