Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni.

Thavy Long,Colette Dissous,Brian M Suzuki,Rachel Beasley,Rahul Singh,William J Zuercher,Matthew P Jacobson,James H Mckerrow,Conor R Caffrey,Chakrapani Kalyanaraman,David H Drewry,R Jeffrey Neitz,Timothy G Geary

doi:10.1371/journal.pntd.0004356

Abstract

BackgroundSchistosoma flatworm parasites cause schistosomiasis, a chronic and debilitating disease of poverty in developing countries. Praziquantel is employed for treatment and disease control. However, its efficacy spectrum is incomplete (less active or inactive against immature stages of the parasite) and there is a concern of drug resistance. Thus, there is a need to identify new drugs and drug targets.Methodology/Principal FindingsWe show that RNA interference (RNAi) of the Schistosoma mansoni ortholog of human polo-like kinase (huPLK)1 elicits a deleterious phenotypic alteration in post-infective larvae (schistosomula or somules). Phenotypic screening and analysis of schistosomula and adult S. mansoni with small molecule inhibitors of huPLK1 identified a number of potent anti-schistosomals. Among these was a GlaxoSmithKline (GSK) benzimidazole thiophene inhibitor that has completed Phase I clinical trials for treatment of solid tumor malignancies. We then obtained GSKs Published Kinase Inhibitor Sets (PKIS) 1 and 2, and phenotypically screened an expanded series of 38 benzimidazole thiophene PLK1 inhibitors. Computational analysis of controls and PLK1 inhibitor-treated populations of somules demonstrated a distinctive phenotype distribution. Using principal component analysis (PCA), the phenotypes exhibited by these populations were mapped, visualized and analyzed through projection to a low-dimensional space. The phenotype distribution was found to have a distinct shape and topology, which could be elicited using cluster analysis. A structure-activity relationship (SAR) was identified for the benzimidazole thiophenes that held for both somules and adult parasites. The most potent inhibitors produced marked phenotypic alterations at 1–2 μM within 1 h. Among these were compounds previously characterized as potent inhibitors of huPLK1 in cell assays.Conclusions/SignificanceThe reverse genetic and chemical SAR data support a continued investigation of SmPLK1 as a possible drug target and/or the prosecution of the benzimidazole thiophene chemotype as a source of novel anti-schistosomals.

Highlights

Flatworm parasites of the Schistosoma genus are responsible for schistosomiasis, a chronic and often painful disease of poverty that affects more than 200 million people worldwide [1,2,3]
In the search for new drugs and drug targets, we have been interested in the schistosome version of human polo-like kinase1, an enzyme with critical functions in cell division
We used RNA interference to knock down messenger RNA for the SmPLK1 –the Schistosoma mansoni parasite’s version of huPLK1

Summary

Introduction

Flatworm parasites of the Schistosoma genus are responsible for schistosomiasis, a chronic and often painful disease of poverty that affects more than 200 million people worldwide [1,2,3]. Apart from the concern over the possible emergence and establishment of resistance to this drug in the field [4, 7,8,9], PZQ has a number of other problems that encourage the search for alternate drugs. It is rarely curative at the single dose employed [10, 11] in part due to its rapid metabolism [12, 13], and the dose used is high (40 mg/kg) relative to other oral anthelmintics and medications in general. There is a need to identify new drugs and drug targets

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Discussion

Conclusion