Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.12530/32160
Title: New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumor cell survival.
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Issue Date: 2-Jun-2017
Citation: Nucleic Acids Res..2017 Jun;(45)10:5797-5817
Abstract: Comparative modeling of the DNA-binding domain of human HSF1 facilitated the prediction of possible binding pockets for small molecules and definition of corresponding pharmacophores. In silico screening of a large library of lead-like compounds identified a set of compounds that satisfied the pharmacophoric criteria, a selection of which compounds was purchased to populate a biased sublibrary. A discriminating cell-based screening assay identified compound 001, which was subjected to systematic analysis of structure-activity relationships, resulting in the development of compound 115 (IHSF115). IHSF115 bound to an isolated HSF1 DNA-binding domain fragment. The compound did not affect heat-induced oligomerization, nuclear localization and specific DNA binding but inhibited the transcriptional activity of human HSF1, interfering with the assembly of ATF1-containing transcription complexes. IHSF115 was employed to probe the human heat shock response at the transcriptome level. In contrast to earlier studies of differential regulation in HSF1-naïve and -depleted cells, our results suggest that a large majority of heat-induced genes is positively regulated by HSF1. That IHSF115 effectively countermanded repression in a significant fraction of heat-repressed genes suggests that repression of these genes is mediated by transcriptionally active HSF1. IHSF115 is cytotoxic for a variety of human cancer cell lines, multiple myeloma lines consistently exhibiting high sensitivity.
PMID: 28369544
URI: https://hdl.handle.net/20.500.12530/32160
Rights: openAccess
Appears in Collections:Fundaciones e Institutos de Investigación > IIS H. U. La Paz > Artículos
Hospitales > H. U. La Paz > Artículos

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