New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumor cell survival

Nucleic Acids Res. 2017 Jun 2;45(10):5797-5817. doi: 10.1093/nar/gkx194.


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.

MeSH terms

  • A549 Cells
  • Acrylamides / chemistry
  • Acrylamides / pharmacology*
  • Activating Transcription Factor 1 / genetics
  • Activating Transcription Factor 1 / metabolism
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • HeLa Cells
  • Heat Shock Transcription Factors
  • Heat-Shock Response / drug effects*
  • Hep G2 Cells
  • High-Throughput Screening Assays
  • Hot Temperature
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Domains
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structural Homology, Protein
  • Structure-Activity Relationship
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transcriptome


  • ATF1 protein, human
  • Acrylamides
  • Activating Transcription Factor 1
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • I(HSF)115 compound
  • Ligands
  • Small Molecule Libraries
  • Thiazoles
  • Transcription Factors