Martin Philpott

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Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to(More)
Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression. BET proteins are recruited on transcriptionally active chromatin via their two N-terminal bromodomains (BRD), a protein interaction(More)
Diet-related mutagenesis plays an etiologic role in chronic diseases, including cardiovascular disease and cancer. Many dietary mutagens are DNA reactive, leading to distinct spectra of base-pair substitution mutations and structural chromosome changes. Examples include aflatoxin B1, ochratoxin A, ptaquiloside, various pyrrolizidine alkaloids, heterocyclic(More)
Bromodomain protein 4 (BRD4) is a member of the bromodomain and extra-terminal domain (BET) protein family. It binds to acetylated histone tails via its tandem bromodomains BD1 and BD2 and forms a complex with the positive transcription elongation factor b, which controls phosphorylation of RNA polymerase II, ultimately leading to stimulation of(More)
BACKGROUND Single nucleotide polymorphisms (SNPs) in the multidrug transporter MDR1 have been associated with inflammatory bowel disease (IBD) in different studies. However, the data are highly controversial. Recently, 6 haplotype tagging SNPs (tSNPs), representing the haplotype variations of the MDR1 gene, were identified. The aims of this study were to(More)
Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which(More)
Acetylation of lysine residues in histone tails plays an important role in the regulation of gene transcription. Bromdomains are the readers of acetylated histone marks, and, consequently, bromodomain-containing proteins have a variety of chromatin-related functions. Moreover, they are increasingly being recognised as important mediators of a wide range of(More)
Many of the cancers common in the Western world, including colon, prostate and breast cancers, are thought to relate to dietary habits. Of the known risk factors, many will act through increasing the probability of mutation. Recognised dietary mutagens include cooked meat compounds, N-nitroso compounds and fungal toxins, while high meat and saturated fat(More)
Ultraviolet B (UVB) light is the principal aetiological factor associated with non-melanoma skin cancer, the most prevalent group of malignancies in the Caucasian population. Exposure to environmental chemicals has also been shown to promote skin carcinogenesis and, as for UVB, this is associated with the acquisition of genomic DNA damage. Cells respond to(More)
Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and(More)