A chemical genomics approach to drug reprofiling in oncology: Antipsychotic drug risperidone as a potential adenocarcinoma treatment

Suzanne J Dilly; Andrew J Clark; Andrew Marsh; Daniel A Mitchell; Ricky Cain; Colin W G Fishwick; Paul C Taylor

doi:10.1016/j.canlet.2017.01.042

A chemical genomics approach to drug reprofiling in oncology: Antipsychotic drug risperidone as a potential adenocarcinoma treatment

Cancer Lett. 2017 May 1:393:16-21. doi: 10.1016/j.canlet.2017.01.042. Epub 2017 Feb 8.

Authors

Suzanne J Dilly¹, Andrew J Clark², Andrew Marsh², Daniel A Mitchell³, Ricky Cain⁴, Colin W G Fishwick⁴, Paul C Taylor⁵

Affiliations

¹ ValiRx plc, 3rd Floor, 16 Upper Woburn Place, London, WC1H 0BS, UK.
² Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
³ Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
⁴ School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
⁵ School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK. Electronic address: p.c.taylor@leeds.ac.uk.

PMID: 28188816
DOI: 10.1016/j.canlet.2017.01.042

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.

Keywords: 17-β-Hydroxysteroid dehydrogenase 10; Adenocarcinoma; Chemical genomics; Drosophila melanogaster; Drug reprofiling.

MeSH terms

17-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
17-Hydroxysteroid Dehydrogenases / chemistry
17-Hydroxysteroid Dehydrogenases / genetics
17-Hydroxysteroid Dehydrogenases / metabolism
3-Hydroxyacyl CoA Dehydrogenases / antagonists & inhibitors*
3-Hydroxyacyl CoA Dehydrogenases / chemistry
3-Hydroxyacyl CoA Dehydrogenases / genetics
3-Hydroxyacyl CoA Dehydrogenases / metabolism
Adenocarcinoma / drug therapy*
Adenocarcinoma / enzymology
Adenocarcinoma / genetics
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Antipsychotic Agents / chemistry
Antipsychotic Agents / pharmacology*
Bacteriophage T7 / genetics
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drosophila melanogaster / drug effects*
Drosophila melanogaster / enzymology
Drosophila melanogaster / genetics
Drug Compounding
Drug Repositioning / methods*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Gene Library
Genomics / methods*
Humans
Linoleic Acids, Conjugated / chemistry
Male
Mice, Nude
Molecular Docking Simulation
Molecular Targeted Therapy
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / enzymology
Prostatic Neoplasms / genetics
Protein Conformation
Risperidone / chemistry
Risperidone / pharmacology*
Structure-Activity Relationship
Time Factors
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Antipsychotic Agents
Enzyme Inhibitors
Linoleic Acids, Conjugated
9,11-linoleic acid
17 beta-hydroxysteroid dehydrogenase type 10, Drosophila
17-Hydroxysteroid Dehydrogenases
3-Hydroxyacyl CoA Dehydrogenases
HSD17B10 protein, human
Risperidone