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PLoS Negl Trop Dis. 2016 Jan 11;10(1):e0004356. doi: 10.1371/journal.pntd.0004356. eCollection 2016 Jan.

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

Author information

1
Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, San Francisco, California, United States of America.
2
Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.
3
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.
4
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.
5
Department of Computer Science, San Francisco State University, San Francisco, California, United States of America.
6
Center of Infection and Immunity of Lille, Université Lille Nord de France, Inserm U1019, CNRS-UMR 8204, Institut Pasteur de Lille, Lille, France.
7
Department of Chemical Biology, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.

Abstract

BACKGROUND:

Schistosoma 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 FINDINGS:

We 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/SIGNIFICANCE:

The 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.

PMID:
26751972
PMCID:
PMC4709140
DOI:
10.1371/journal.pntd.0004356
[Indexed for MEDLINE]
Free PMC Article

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