I-BET151

BET家族抑制剂；抑制BRD2，BRD3和BRD4

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产品号 #73712_C

BET家族抑制剂；抑制BRD2，BRD3和BRD4

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总览

I-BET151是溴结构域和额外末端（BET）家族蛋白的抑制剂。BET蛋白通过其2个溴结构域识别乙酰化赖氨酸残基（Gallenkamp et al.）。I-BET151抑制BRD2、BRD3和BRD4，IC₅₀值分别为0.5、0.25和0.79µM (Kline et al.; Vidler et al.; Hewings et al.; Dawson et al. 2012)。

重编程
·与ISX-9、Forskolin和CHIR99021联合，可增强小鼠成纤维细胞向神经元的重编程（Li et al.）。

癌症研究
·通过阻断BCL2、C-MYC和CDK6等关键基因的转录，诱导人和小鼠MLL融合白血病细胞系的早期细胞周期阻滞和凋亡（Dawson et al. 2011）。

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Document Type

Product Name

Catalog #

Lot #

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Document Type

Product Information Sheet

Product Name

I-BET151

Catalog #

73712, 73714

Lot #

All

Language

English

Document Type

Safety Data Sheet

Product Name

I-BET151

Catalog #

73712, 73714

Lot #

All

Language

English

Abstract

Recently, direct reprogramming between divergent lineages has been achieved by the introduction of regulatory transcription factors. This approach may provide alternative cell resources for drug discovery and regenerative medicine, but applications could be limited by the genetic manipulation involved. Here, we show that mouse fibroblasts can be directly converted into neuronal cells using only a cocktail of small molecules, with a yield of up to textgreater90% being TUJ1-positive after 16 days of induction. After a further maturation stage, these chemically induced neurons (CiNs) possessed neuron-specific expression patterns, generated action potentials, and formed functional synapses. Mechanistically, we found that a BET family bromodomain inhibitor, I-BET151, disrupted the fibroblast-specific program, while the neurogenesis inducer ISX9 was necessary to activate neuron-specific genes. Overall, our findings provide a proof of principle" for chemically induced direct reprogramming of somatic cell fates across germ layers without genetic manipulation�

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Bromodomains and their pharmacological inhibitors. Gallenkamp D et al. ChemMedChem 2014 MAR

Abstract

Over 60 bromodomains belonging to proteins with very different functions have been identified in humans. Several of them interact with acetylated lysine residues, leading to the recruitment and stabilization of protein complexes. The bromodomain and extra-terminal domain (BET) proteins contain tandem bromodomains which bind to acetylated histones and are thereby implicated in a number of DNA-centered processes, including the regulation of gene expression. The recent identification of inhibitors of BET and non-BET bromodomains is one of the few examples in which effective blockade of a protein-protein interaction can be achieved with a small molecule. This has led to major strides in the understanding of the function of bromodomain-containing proteins and their involvement in diseases such as cancer and inflammation. Indeed, BET bromodomain inhibitors are now being clinically evaluated for the treatment of hematological tumors and have also been tested in clinical trials for the relatively rare BRD-NUT midline carcinoma. This review gives an overview of the newest developments in the field, with a focus on the biology of selected bromodomain proteins on the one hand, and on reported pharmacological inhibitors on the other, including recent examples from the patent literature.

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Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. Hewings DS et al. Journal of medicinal chemistry 2013 APR

Abstract

The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.

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