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

• Nuria Vilaboa ^[1] ; Alba Boré ^[1] ; Francisco Martin-Saavedra ^[1] ; Melanie Bayford ^[3] ; Natalie Winfield ^[3] ; Stuart Firth-Clark ^[3] ; Stewart B. Kirton ^[2] ; Richard Voellmy ^[4]
  1. [1] Hospital Universitario La Paz

     Hospital Universitario La Paz

     Madrid, España

     
  2. [2] University of Hertfordshire

     University of Hertfordshire

     Welwyn Hatfield, Reino Unido

     
  3. [3] Domainex Ltd, Chesterford Research Park, Little Chesterford, Saffron Walden, Essex CB10 1XL, UK
  4. [4] HSF Pharmaceuticals SA, 1814 La Tour-de-Peilz, Switzerland

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• Localización: Nucleic acids research, ISSN 0305-1048, Vol. 45, Nº. 10, 2017, págs. 5797-5817
• Idioma: inglés
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  • 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.