title: New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumor cell survival.
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.
authors.affiliation: Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain.|CIBER de Bioingenieria, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Vilaboa
authors.affiliation: Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain.|CIBER de Bioingenieria, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Boré
authors.affiliation: Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain.|CIBER de Bioingenieria, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Martin-Saavedra
authors.affiliation: Domainex Ltd, Chesterford Research Park, Little Chesterford, Saffron Walden, Essex CB10 1XL, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bayford
authors.affiliation: Domainex Ltd, Chesterford Research Park, Little Chesterford, Saffron Walden, Essex CB10 1XL, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Winfield
authors.affiliation: Domainex Ltd, Chesterford Research Park, Little Chesterford, Saffron Walden, Essex CB10 1XL, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Firth-Clark
authors.affiliation: University of Hertfordshire, Hatfield, Hertfordshire, AL10 9AB, UK.
authors.forename: Stewart B
authors.initials: SB
authors.lastname: Kirton
authors.affiliation: HSF Pharmaceuticals SA, 1814 La Tour-de-Peilz, Switzerland.
authors.forename: Richard
authors.initials: R
authors.lastname: Voellmy
mesh_terms: D000072283:A549 Cells; D000178:Acrylamides / Q000737:chemistry / Q000494:pharmacology*; D051697:Activating Transcription Factor 1 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000187:drug effects*; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays; D006358:Hot Temperature; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D000072417:Protein Domains; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: C531110:ATF1 protein, human; D000178:Acrylamides; D051697:Activating Transcription Factor 1; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C000622633:I(HSF)115 compound; D008024:Ligands; D054852:Small Molecule Libraries; D013844:Thiazoles; D014157:Transcription Factors