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dc.contributor.authorKirton, Stewart
dc.date.accessioned2018-08-16T00:11:52Z
dc.date.available2018-08-16T00:11:52Z
dc.date.issued2017-03-21
dc.identifier.citationKirton , S 2017 , ' New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumour cell survival. ' , Nucleic Acids Research . https://doi.org/10.1093/nar/gkx194
dc.identifier.issn0305-1048
dc.identifier.otherPURE: 11324938
dc.identifier.otherPURE UUID: 04e6e21b-52f4-4067-ba6d-e6b941c8dd79
dc.identifier.otherScopus: 85021359678
dc.identifier.urihttp://hdl.handle.net/2299/20368
dc.description© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Nuria Vilabo, Alba Bore, Francisco Martin-Saavedra, Melanie Bayford, Natalie Winfield, Stuart Firth-Clark, Stewart B. Kirton, and Richard Voellmy, 'New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumor cell survival', Nucleic Acids Research, 2017, 1, doi: 10.1093/nar/gkx194
dc.description.abstractComparative 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.en
dc.language.isoeng
dc.relation.ispartofNucleic Acids Research
dc.subjecttranscription
dc.subjectgenetic
dc.subjectcell survival
dc.subjectDNA
dc.subjectgenes
dc.subjectheat (physical force)
dc.subjectheat-shock reponse
dc.subjectinterleukin-6
dc.subjectneoplasms
dc.subjecttranscriptino factor
dc.subjecttumor cells
dc.subjectmalignant
dc.subjectmolecule
dc.titleNew inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumour cell survival.en
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionDepartment of Pharmacy, Pharmacology and Postgraduate Medicine
dc.contributor.institutionCentre for Research into Topical Drug Delivery and Toxicology
dc.contributor.institutionNatural Product Chemistry and Drug Design
dc.contributor.institutionMedicinal and Analytical Chemistry
dc.contributor.institutionPsychopharmacology, Drug Misuse and Novel Psychoactive Substances Unit
dc.contributor.institutionCentre for Health Services and Clinical Research
dc.description.statusPeer reviewed
rioxxterms.versionVoR
rioxxterms.versionofrecordhttps://doi.org/10.1093/nar/gkx194
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue


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