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 DNAbinding 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-na¨ıve 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, multiplemyeloma lines consistently exhibiting high sensitivity.
Original languageEnglish
JournalNucleic Acids Research
Early online date21 Mar 2017
DOIs
Publication statusE-pub ahead of print - 21 Mar 2017

Keywords

  • transcription
  • genetic
  • cell survival
  • DNA
  • genes
  • heat (physical force)
  • heat-shock reponse
  • interleukin-6
  • neoplasms
  • transcriptino factor
  • tumor cells
  • malignant
  • molecule

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