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54 Publications

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    Sternson Lab
    04/11/02 | Dissecting glucose signalling with diversity-oriented synthesis and small-molecule microarrays.
    Kuruvilla FG, Shamji AF, Sternson SM, Hergenrother PJ, Schreiber SL
    Nature. 2002 Apr 11;416(6881):653-7. doi: 10.1038/416653a

    Small molecules that alter protein function provide a means to modulate biological networks with temporal resolution. Here we demonstrate a potentially general and scalable method of identifying such molecules by application to a particular protein, Ure2p, which represses the transcription factors Gln3p and Nil1p. By probing a high-density microarray of small molecules generated by diversity-oriented synthesis with fluorescently labelled Ure2p, we performed 3,780 protein-binding assays in parallel and identified several compounds that bind Ure2p. One compound, which we call uretupamine, specifically activates a glucose-sensitive transcriptional pathway downstream of Ure2p. Whole-genome transcription profiling and chemical epistasis demonstrate the remarkable Ure2p specificity of uretupamine and its ability to modulate the glucose-sensitive subset of genes downstream of Ure2p. These results demonstrate that diversity-oriented synthesis and small-molecule microarrays can be used to identify small molecules that bind to a protein of interest, and that these small molecules can regulate specific functions of the protein.

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    Sternson Lab
    12/27/01 | Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin.
    Sternson SM, Wong JC, Grozinger CM, Schreiber SL
    Organic Letters. 2001 Dec 27;3(26):4239-42

    Seventy-two hundred potential inhibitors of the histone deacetylase (HDAC) enzyme family, based on a 1,3-dioxane diversity structure, were synthesized on polystyrene macrobeads. The compounds were arrayed for biological assays in a "one bead-one stock solution" format. Metal-chelating functional groups were used to direct the 1,3-dioxanes to HDAC enzymes, which are zinc hydrolases. Representative structures from this library were tested for inhibitory activity and the 1,3-dioxane structure was shown to be compatible with HDAC inhibition. [structure: see text]

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    Sternson Lab
    02/28/01 | Split--pool synthesis of 1,3-dioxanes leading to arrayed stock solutions of single compounds sufficient for multiple phenotypic and protein-binding assays.
    Sternson SM, Louca JB, Wong JC, Schreiber SL
    Journal of the American Chemical Society. 2001 Feb 28;123(8):1740-7

    Diversity-oriented organic synthesis offers the promise of advancing chemical genetics, where small molecules are used to explore biology. While the split--pool synthetic method is theoretically the most effective approach for the production of large collections of small molecules, it has not been widely adopted due to numerous technical and analytical hurdles. We have developed a split--pool synthesis leading to an array of stock solutions of single 1,3-dioxanes. The quantities of compounds are sufficient for hundreds of phenotypic and protein-binding assays. The average concentration of these stock solutions derived from a single synthesis bead was determined to be 5.4 mM in 5 microL of DMSO. A mass spectrometric strategy to identify the structure of molecules from a split--pool synthesis was shown to be highly accurate. Individual members of the 1,3-dioxane library have activity in a variety of phenotypic and protein-binding assays. The procedure developed in this study allows many assays to be performed with compounds derived from individual synthesis beads. The synthetic compounds identified in these assays should serve as useful probes of cellular and organismal processes.

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    Sternson Lab
    10/08/98 | An acid- and base-stable o-nitrobenzyl photolabile linker for solid phase organic synthesis.
    Sternson SM, Schreiber SL
    Tetrahedron Letters. 1998 Oct 8;39:7451-54

    The synthesis of an o-nitrobenzyl photolabile linker (1) from o-nitrobenzaldehyde is described, and the efficiency of its light-mediated (365 nm) cleavage is found to be comparable to related, previously developed systems. In contrast, 1 is shown to be stable to acid, base, and Lewis acid/amine combinations while the previously developed linker 2 is shown to degrade under the latter two conditions.

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