2013
DOI: 10.1021/jm301793a
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Abstract: Recognizing acetyllysine of histone is a vital process of epigenetic regulation that is mediated by a protein module called bromodomain. To contribute novel scaffolds for developing into bromodomain inhibitors, we utilize a fragment-based drug discovery approach. By successively applying docking and X-ray crystallography, we were able to identify 9 fragment hits from diffracting more than 60 crystals. In the present work, we described four of them and carried out the integrated lead optimization for fragment 8… Show more

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Cited by 108 publications
(108 citation statements)
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“…In addition, Tax-transformed lymphoid cells and fibroblasts form tumors in immunodeficient mice (5,6). Moreover, Tax is directly required for establishment and maintenance of the transformed phenotype because the HTLV-1 genome without Tax loses its original transforming ability (7). Furthermore, Tax-transgenic mice developed tumors and several inflammatory diseases (6).…”
Section: Human T Cell Leukemia Virus 1 (Htlv-1)mentioning
confidence: 99%
“…In addition, Tax-transformed lymphoid cells and fibroblasts form tumors in immunodeficient mice (5,6). Moreover, Tax is directly required for establishment and maintenance of the transformed phenotype because the HTLV-1 genome without Tax loses its original transforming ability (7). Furthermore, Tax-transgenic mice developed tumors and several inflammatory diseases (6).…”
Section: Human T Cell Leukemia Virus 1 (Htlv-1)mentioning
confidence: 99%
“…As might be predicted from the crystal structure, para-or meta-chlorine substitution (3 and 19) afforded similarly potent compounds in both biochemical and cellular assays. ortho-Chloro substitution (20) led to a 10-fold drop in biochemical potency, perhaps because this substitution induced an unfavorable twist between the two unsaturated systems. However, the ortho-methyl and para-chloro substitutions (23) were tolerated, leading to a compound with potency similar to that of the parent, suggesting that the ortho-chloro substituent was not tolerated due to an unfavorable electrostatic interaction, rather than a steric one.…”
mentioning
confidence: 99%
“…Protein samples of the first bromodomain of BRD4 (BRD4(I): BRD4 N-terminal fragment spanning N44 to E168) were prepared as previously described [27,28] . His-tagged BRD4(I) was expressed in Escherichia coli [BL21(DE3) competent cells] and purified by using a combination of affinity chromatography (Ni-NTA column) and size exclusion chromatography (HiLoad 16/600 Superdex 75 pg column) on an FPLC system.…”
Section: Protein Sample Preparationmentioning
confidence: 99%