Journal article
Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni
PLoS neglected tropical diseases, Vol.10(1), pp.e0004356-e0004356
01/01/2016
DOI: 10.1371/journal.pntd.0004356
PMCID: PMC4709140
PMID: 26751972
Abstract
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.
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.
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.
Details
- Title: Subtitle
- Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni
- Creators
- Thavy Long - University of California, San FranciscoR Jeffrey Neitz - University of California, San FranciscoRachel Beasley - San Francisco State UniversityChakrapani Kalyanaraman - University of California, San FranciscoBrian M Suzuki - University of California, San FranciscoMatthew P Jacobson - University of California, San FranciscoColette Dissous - Center for Infection and Immunity of LilleJames H McKerrow - University of California, San FranciscoDavid H Drewry - Research Triangle Park FoundationWilliam J Zuercher - Research Triangle Park FoundationRahul Singh - University of California, San FranciscoConor R Caffrey - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- PLoS neglected tropical diseases, Vol.10(1), pp.e0004356-e0004356
- DOI
- 10.1371/journal.pntd.0004356
- PMID
- 26751972
- PMCID
- PMC4709140
- NLM abbreviation
- PLoS Negl Trop Dis
- ISSN
- 1935-2727
- eISSN
- 1935-2735
- Grant note
- R21 AI107390 / NIAID NIH HHS 1R01AI089896 / NIAID NIH HHS R21AI107390 / NIAID NIH HHS R01 AI089896 / NIAID NIH HHS
- Language
- English
- Date published
- 01/01/2016
- Academic Unit
- Computer Science
- Record Identifier
- 9984446441502771
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