2016
DOI: 10.1002/cmdc.201600528
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Potent and Selective Non‐hydroxamate Histone Deacetylase 8 Inhibitors

Abstract: Specific inhibition of histone deacetylase 8 (HDAC8) has been suggested as a promising option for the treatment of neuroblastoma and T-cell malignancies. A novel class of highly potent and selective HDAC8 inhibitors with a pyrimido[1,2-c][1,3]benzothiazin-6-imine scaffold was studied that is completely different from the traditional concept of HDAC inhibitors comprising a zinc binding group (ZBG), in most cases a hydroxamate group, a spacer, and a capping group that may interact with the surface of the target … Show more

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Cited by 33 publications
(17 citation statements)
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“…In ap revious study,w eidentified PD-404,182 as ap otent and selectiveH DAC8 inhibitor. [19] By using time resolved HPLC-MS/ MS, we also explained the exact mechanism of PD-404,182 decomposition in aqueous solution and subsequent mixed disulfide formation of various cysteines in HDAC8. [20] PD-404,182 decomposes quicklyi nto the corresponding sulfenamide, which forms mixed disulfides with cysteiner esidues for example, in HDAC8.…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…In ap revious study,w eidentified PD-404,182 as ap otent and selectiveH DAC8 inhibitor. [19] By using time resolved HPLC-MS/ MS, we also explained the exact mechanism of PD-404,182 decomposition in aqueous solution and subsequent mixed disulfide formation of various cysteines in HDAC8. [20] PD-404,182 decomposes quicklyi nto the corresponding sulfenamide, which forms mixed disulfides with cysteiner esidues for example, in HDAC8.…”
Section: Resultsmentioning
confidence: 99%
“…[12][13][14][15][16][17][18] In the effort to discover new potent and selective non-hydroxamate inhibitors of HDAC8, we identified PD-404,182 in amedium-scaled compound screeningc ampaign. [19] Further studies on the mode of protein-inhibitor interaction revealedt hat PD-404,182 is ac ovalent modifier of HDAC8, forms mixed disulfides and transformst hiol groups into thiocyanates. [20] In af urther study we found that HDAC8 is regulated by ar edox switchi nvolving cysteines Cys 102 and Cys 153 .…”
Section: Introductionmentioning
confidence: 99%
“…A concentration series of a reference inhibitor like SAHA, trichostatin A, or SATFMK is highly recommended Add 10 μl HDAC/HDAH working solution to each well and incubate for 30 min to detect also slow binding inhibitors Add 20 μl of a mixture containing 100 μM substrate and 0.5 mg/ml trypsin Start the fluorescence measurement of continuously released AMC for a period of about 30–60 min immediately. The slope of fluorescence intensity versus time is proportional to enzyme activity ExampleFigure : Dose–response curves of selected benzothiazine‐6‐imine inhibitors of HDAC8 (Kleinschek, Meyners, Digiorgio, Brancolini, & Meyer‐Almes, )…”
Section: Methodsmentioning
confidence: 99%
“…Start the fluorescence measurement of continuously released AMC for a period of about 30-60 min immediately. The slope of fluorescence intensity versus time is proportional to enzyme activity Example Figure 6: Dose-response curves of selected benzothiazine-6-imine inhibitors of HDAC8 (Kleinschek, Meyners, Digiorgio, Brancolini, & Meyer-Almes, 2016) Figures 5 and 6.…”
Section: Notesmentioning
confidence: 99%
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