CFU‐MK Assay for Acute Thrombocytopenia

Parent‐Massin, D.; Sibiril, Y.

doi:10.1002/0471140856.tx2005s37

Cited by 2 publications

(1 citation statement)

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“…We used our HDACi tool kit to measure megakaryocyte colony formation in human CD34 + progenitor cells, 45 an assay predictive of thrombocytopenia. 46,47 Consistent with reported clinical toxicity, CI-994 strongly inhibited megakaryocyte colony formation in a dose-dependent manner, while the negative control compound, BRD4097, had no effect on this cell population, clearly demonstrating an "on-mechanism" effect of HDAC inhibition (Figure 7a,b). Similar inhibition of colony formation was observed with 1 and 10 μM BRD2492, the HDAC1,2 selective inhibitor, implicating these isoforms.…”

Section: ■ Results and Discussionsupporting

confidence: 78%

An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection

et al. 2015

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Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it has been difficult to dissect the role of individual HDACs due to a lack of selective small-molecule inhibitors. Here, we report the synthesis of a series of highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes to the clinically experienced HDAC inhibitor CI-994. We used this toolkit of isochemogenic or chemically matched inhibitors to probe the role of class I HDACs in β-cell pathobiology and demonstrate for the first time that selective inhibition of an individual HDAC isoform retains beneficial biological activity and mitigates mechanism-based toxicities. The highly selective HDAC3 inhibitor BRD3308 suppressed pancreatic β-cell apoptosis induced by inflammatory cytokines, as expected, or now glucolipotoxic stress, and increased functional insulin release. In addition, BRD3308 had no effect on human megakaryocyte differentiation, while inhibitors of HDAC1 and 2 were toxic. Our findings demonstrate that the selective inhibition of HDAC3 represents a potential path forward as a therapy to protect pancreatic β-cells from inflammatory cytokines and nutrient overload in diabetes.

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Section: ■ Results and Discussionsupporting

confidence: 78%