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

Highlights

• Demonstration that our Magic Tag^® chemical genomics platform can be used to “reprofile” drugs into cancer indications.

• The use of fruit fly Drosophila melanogaster as an unusual model organism for cancer drug discovery.

• The further exploration of 17-β-hydroxysteroid dehydrogenase 10 as an emerging cancer target.

• The potential of VAL401 as a candidate for clinical trials in adenocarcinomas.

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.

Introduction

In the search for new cancer treatments, the potential of existing drugs that have been or are being used for non-cancer indications remains under-investigated [1]. Drug reprofiling (or repurposing or repositioning), is a commercially attractive route to new therapies, since it reduces risks in the development process by exploiting the well-known safety and pharmacokinetic profiles of the drugs [2]. In oncology, reprofiling successes include thalidomide (anti-emetic to multiple myeloma) and zoledronic acid (anti-bone resorption to multiple myeloma, prostate cancer and breast cancer) [3].

Recently, systematic experimental [4] and in silico [5] approaches to reprofiling for oncology have emerged. Our Magic Tag^® chemical genomics tool was designed to link the known biological activity of an organic chemical with the genome as expressed through a phage displayed library of polypeptides [6], [7]. Herein we demonstrate that Magic Tag^® has the potential to be a new and complementary method for systematically screening known drugs to identify reprofiling opportunities. Specifically, we present the widely used antipsychotic therapy risperidone as a possible treatment for prostate cancer and other adenocarcinomas.

Antipsychotic drugs such as chlorpromazine 1, clozapine 2 and risperidone 3 have long been known to display polypharmacology [8]. Known to have multiple protein targets, such drugs are interesting candidates for drug reprofiling. We decided to photoimmobilise one drug from this class, chlorpromazine 1, using Magic Tag^® and screen it against a library of polypeptides displayed on T7 bacteriophage, as previously described [7].

For drug reprofiling, a whole genome model is needed; we elected, as in our previous study of flecainide acetate, to use a display library originating from Drosophila melanogaster [9]. Despite its central importance to developments in both genetics and genomics, the common fruit fly, D. melanogaster, is underexploited in the field of drug discovery [10], [11]. Around 60% of D. melanogaster genes have human orthologues [12]. Significantly, around three quarters of genes related to human disease states have orthologues in D. melanogaster [7] and all major human signalling pathways are present in D. melanogaster [10].