title: A yeast chemical genetics approach identifies the compound 3,4,5-trimethoxybenzyl isothiocyanate as a calcineurin inhibitor.
abstract: The phosphatase enzyme calcineurin controls gene expression in a variety of biological contexts however few potent inhibitors are currently available. A screen of 360 plant extracts for inhibition of calcineurin-dependent gene expression in the model organism Saccharomyces cerevisiae identified the compound 3,4,5-trimethoxybenzyl isothiocyanate as an inhibitor. The compound was subsequently shown to inhibit human calcineurin via a mixed inhibition mechanism. To gain further mechanistic insight a yeast haploinsufficiency screen of 1152 deletion strains was carried out using a novel liquid medium screening method. The resulting haploinsufficiency profile is similar to that reported for the known calcineurin inhibitor FK506.
authors.affiliation: Royal Botanic Gardens, Kew, Richmond, Surrey TW9 3AB, UK. Electronic address: t.prescott@kew.org.
authors.forename: Thomas A K
authors.initials: TA
authors.lastname: Prescott
authors.affiliation: Institute of Pharmaceutical Science, Franklin-Wilkins Building, London SE1 9NH, UK. Electronic address: barry.panaretou@kcl.ac.uk.
authors.forename: Barry
authors.initials: B
authors.lastname: Panaretou
authors.affiliation: Royal Botanic Gardens, Kew, Richmond, Surrey TW9 3AB, UK.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Veitch
authors.affiliation: Royal Botanic Gardens, Kew, Richmond, Surrey TW9 3AB, UK.
authors.forename: Monique S J
authors.initials: MS
authors.lastname: Simmonds
mesh_terms: D019703:Calcineurin / Q000096:biosynthesis*; D065095:Calcineurin Inhibitors; D002460:Cell Line; D004791:Enzyme Inhibitors; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D010936:Plant Extracts; D005707:Gallic Acid; D019703:Calcineurin; C005854:3,4,5-trimethoxybenzoic acid; D016559:Tacrolimus
keywords: 3,4,5-Trimethoxybenzyl isothiocyanate; Calcineurin; Haploinsufficiency screen; Iberis saxatilis; Yeast