Danny Hung-Chieh Chou

Broad Institute of MIT and Harvard, Cambridge, MA, United States

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Publications (4)15.28 Total impact

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    ABSTRACT: Cytokine-induced beta-cell apoptosis is important to the etiology of type-1 diabetes. Although previous reports have shown that general inhibitors of histone deacetylase (HDAC) activity, such as suberoylanilide hydroxamic acid and trichostatin A, can partially prevent beta-cell death, they do not fully restore beta-cell function. To understand HDAC isoform selectivity in beta cells, we measured the cellular effects of 11 structurally diverse HDAC inhibitors on cytokine-induced apoptosis in the rat INS-1E cell line. All 11 compounds restored ATP levels and reduced nitrite secretion. However, caspase-3 activity was reduced only by MS-275 and CI-994, both of which target HDAC1, 2, and 3. Importantly, both MS-275 and genetic knockdown of Hdac3 alone were sufficient to restore glucose-stimulated insulin secretion in the presence of cytokines. These results suggest that HDAC3-selective inhibitors may be effective in preventing cytokine-induced beta-cell apoptosis.
    Chemistry & biology 06/2012; 19(6):669-73. · 6.52 Impact Factor
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    ABSTRACT: The synthesis of a stereochemically diverse library of medium-sized rings accessible via a 'build/couple/pair' strategy is described. Key aspects of the synthesis include S(N)Ar cycloetherification of a linear amine template to afford eight stereoisomeric 8-membered lactams and subsequent solid-phase diversification of these scaffolds to yield a 6488-membered library. Screening of this compound collection in a cell-based assay for the suppression of cytokine-induced beta-cell apoptosis resulted in the identification of a small-molecule suppressor capable of restoring glucose-stimulated insulin secretion in a rat beta-cell line. The presence of all stereoisomers in the screening collection enabled preliminary determination of the structural and stereochemical requirements for cellular activity, while efficient follow-up chemistry afforded BRD-0476 (probe ML187), which had an approximately three-fold increase in activity. These results demonstrate the utility of diversity-oriented synthesis to probe discovery using cell-based screening, and the importance of including stereochemical diversity in screening collections for the development of stereo/structure-activity relationships.
    ACS Medicinal Chemistry Letters 09/2011; 2(9):698-702. · 3.31 Impact Factor
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    ABSTRACT: Pancreatic beta-cell apoptosis is a critical event during the development of type-1 diabetes. The identification of small molecules capable of preventing cytokine-induced apoptosis could lead to avenues for therapeutic intervention. We developed a set of phenotypic cell-based assays designed to identify such small-molecule suppressors. Rat INS-1E cells were simultaneously treated with a cocktail of inflammatory cytokines and a collection of 2,240 diverse small molecules and screened using an assay for cellular ATP levels. Forty-nine top-scoring compounds included glucocorticoids, several pyrazole derivatives, and known inhibitors of glycogen synthase kinase-3beta. Two compounds were able to increase cellular ATP levels, reduce caspase-3 activity and nitrite production, and increase glucose-stimulated insulin secretion in the presence of cytokines. These results indicate that small molecules identified by this screening approach may protect beta cells from autoimmune attack and may be good candidates for therapeutic intervention in early stages of type-1 diabetes.
    ACS Chemical Biology 08/2010; 5(8):729-34. · 5.44 Impact Factor
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    ABSTRACT: Type 1 diabetes is caused by autoimmune destruction of insulin-producing beta cells in the pancreas. In this process, beta-cell apoptosis involves multiple signaling cascades stimulated by interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). These pathways result in decreased pancreatic beta-cell numbers that lead to the disease phenotype. Most of the compounds described in the literature protect cells from a single facet of cytokine treatment but do not provide wide-ranging protection from apoptosis nor do they restore insulin secretion. The goal of this project was to identify and to optimize small molecules that can prevent cytokine-induced pancreatic beta-cell apoptosis. To achieve this goal, we completed a screen of 339,000 compounds in rat INS-1E insulinoma cells treated with IL-1β, IFN-γ, and TNF-α. As a result, we identified MLS003179189, a member of a novel diversity-oriented synthesis (DOS) library with stereochemical diversity and complexity akin to naturally occurring small molecules. MLS003179189 contains 3 stereocenters and was the only stereoisomer (out of eight possible stereoisomers) to show activity in the primary assay for cell viability. About 50 analogs of the active stereoisomer were synthesized and tested, leading to a superior probe candidate (ML187). In studies with dissociated human primary pancreatic islets, (ML187) improved cell viability, decreased caspase activation, and improved insulin production. These data suggest that a consistent mechanism of action exists in both rat and human cells and that the probe (ML187) is a first-in-class probe for Type I diabetes that both protects against destruction of beta cells and restores function.