I-BET151 is an inhibitor of bromodomain and extra terminal (BET) family proteins. BET proteins recognize acetylated lysine residues via their 2 bromodomains (Gallenkamp et al.). I-BET151 inhibits BRD2, BRD3, and BRD4 with IC₅₀ values of 0.5, 0.25, and 0.79 µM, respectively (Kline et al.; Vidler et al.; Hewings et al.; Dawson et al. 2012).
REPROGRAMMING
· Enhances reprogramming of mouse fibroblasts to neurons, in combination with ISX-9, Forskolin, and CHIR99021 (Li et al.)
CANCER RESEARCH
· Induces early cell cycle arrest and apoptosis in human and mouse MLL-fusion leukemia cell lines by blocking transcription of key genes including BCL2, C-MYC, and CDK6 (Dawson et al. 2011).
REPROGRAMMING
· Enhances reprogramming of mouse fibroblasts to neurons, in combination with ISX-9, Forskolin, and CHIR99021 (Li et al.)
CANCER RESEARCH
· Induces early cell cycle arrest and apoptosis in human and mouse MLL-fusion leukemia cell lines by blocking transcription of key genes including BCL2, C-MYC, and CDK6 (Dawson et al. 2011).
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Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
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Resources and Publications
Publications (7)
Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons. Cell stem cell 2015 AUG
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�
Bromodomains and their pharmacological inhibitors. 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.
Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. 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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