title: Selective killing of cancer cells by small molecules targeting heat shock stress response.
abstract: HSF1 heat shock response has emerged as a valuable non-oncogenetic intervention point in targeted cancer therapy. Current reporter based high throughput screening has led to the discovery of several compounds or chemotypes that are effective in the growth inhibition of multiple cancer cell lines and relevant animal tumor models. However, some intrinsic limitations of reporter based assays can potentially lead to biased results. Using a previously validated high content image based assay, we performed a phenotypic screen targeting HSF1 heat shock pathway with a chemically diversified library of over 100,000 compounds. Several novel functional inhibitors of HSF1 pathway were identified with different chemotypes. Western blot analysis confirmed that selective compounds inhibit phosphorylation of HSF1, followed by reduced expression of HSP proteins. Moreover, HeLa cells stably transfected with HSF1 shRNA were more resistant to the compound treatment under lethal temperature than cells containing HSF1, validating HSF1 dependent mechanism of action. These compounds demonstrate nanomolar potency toward multiple cancer cell lines with relatively low cytotoxicity to normal cells. Further SAR and target identification study will pave the way for the potential development of next generation anticancer drugs.
authors.affiliation: Department of Biology, Alpine Therapeutics, Inc., 13350 Camino Del Sur, No. 8, San Diego, CA 92129, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Biology, Alpine Therapeutics, Inc., 13350 Camino Del Sur, No. 8, San Diego, CA 92129, USA. Electronic address: bzhang418@gmail.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
mesh_terms: D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000187:drug effects*; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D014157:Transcription Factors
keywords: Cancer; Compound inhibitor; HSF1; Heat shock response; High content screening