Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis.

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Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. Abstract Text:

Angela N Koehler,Alykhan F Shamji,Stuart L Schreiber,

Small molecule microarrays were screened to identify a small molecule ligand for Hap3p, a subunit of the yeast Hap2/3/4/5p transcription factor complex. The compound, named haptamide A, was determined to have a KD of 5.03 muM for binding to Hap3p using surface plasmon resonance analysis. Haptamide A also inhibited activation of a GDH1-lacZ reporter gene in a dose-dependent fashion. To explore structure-activity relationships, 11 derivatives of haptamide A were prepared using the same synthetic route that was developed for the original library synthesis. Analysis of dissociation constants and IC50 values for the reporter gene assay revealed a more potent inhibitor, haptamide B, with a KD of 330 nM. Whole-genome transcriptional profiling was used to compare effects of haptamide B with a hap3Delta yeast strain. Treatment with haptamide B, like the deletion mutant, reduced lactate-induced transcription of several genes from wild-type levels. Profiling the genetic "knockout" and the chemical genetic "knockdown" led to the identification of several genes that are regulated by Hap3p under nonfermentative conditions. These results demonstrate that a small molecule discovered using the small molecule microarray binding assay can permeate yeast cells and reach its target transcription factor protein in cells.

Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. Publishing Authors By Initials

AN Koehler,AF Shamji,SL Schreiber,

For similar proteins: transcription factors research abstracts see: proteins: transcription factors research

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Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Journal of the American Chemical Society

VOLUME: 125

Page Numbers: 8420-1

Journal Abbreviation: J. Am. Chem. Soc.

ISSN: 0002-7863

DAY: 16

MONTH: Jul

YEAR: 2003

Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. Information

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LANGUAGE: eng

NlmUniqueID: 7503056

Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. Keywords Mesh Terms:

KEYWORDS: Transcription Factors

MESH TERMS: metabolism

Chemical & Substance for Abstract: Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. Information

Substance Name: Glutathione Transferase

Registry Number: EC 2.5.1.18

Grant and Affiliation Information for Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis.

AFFILIATION: Department of Chemistry and Chemical Biology, Harvard Biophysics Program, Howard Hughes Medical Institute, Harvard Institute of Chemistry and Cell Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.

Country: United States

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MEDLINETA: J Am Chem Soc

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