title: A chemical genomics approach to drug reprofiling in oncology: Antipsychotic drug risperidone as a potential adenocarcinoma treatment.
abstract: Drug reprofiling is emerging as an effective paradigm for discovery of cancer treatments. Herein, an antipsychotic drug is immobilised using the Magic Tag®chemical genomics tool and screened against a T7 bacteriophage displayed library of polypeptides from Drosophila melanogaster, as a whole genome model, to uncover an interaction with a section of 17-β-HSD10, a proposed prostate cancer target. A computational study and enzyme inhibition assay with full length human 17-β-HSD10 identifies risperidone as a drug reprofiling candidate. When formulated with rumenic acid, risperidone slows proliferation of PC3 prostate cancer cells in vitro and retards PC3 prostate cancer tumour growth in vivo in xenografts in mice, presenting an opportunity to reprofile risperidone as a cancer treatment.
authors.affiliation: ValiRx plc, 3rd Floor, 16 Upper Woburn Place, London, WC1H 0BS, UK.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Dilly
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Clark
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Marsh
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Mitchell
authors.affiliation: School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Ricky
authors.initials: R
authors.lastname: Cain
authors.affiliation: School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Colin W G
authors.initials: CWG
authors.lastname: Fishwick
authors.affiliation: School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK. Electronic address: p.c.taylor@leeds.ac.uk.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Taylor
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D017123:Bacteriophage T7 / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D004339:Drug Compounding; D058492:Drug Repositioning / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015723:Gene Library; D023281:Genomics / Q000379:methods*; D006801:Humans; D044243:Linoleic Acids, Conjugated / Q000737:chemistry; D008297:Male; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D011487:Protein Conformation; D018967:Risperidone / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D044243:Linoleic Acids, Conjugated; C046938:9,11-linoleic acid; C479399:17 beta-hydroxysteroid dehydrogenase type 10, Drosophila; D015067:17-Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; D018967:Risperidone
keywords: 17-β-Hydroxysteroid dehydrogenase 10; Adenocarcinoma; Chemical genomics; Drosophila melanogaster; Drug reprofiling