Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni.
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 par...
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ftdoajarticles:oai:doaj.org/article:1f31106f26284b5db634a718d8bb99bb 2023-05-15T15:16:35+02:00 Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni. Thavy Long R Jeffrey Neitz Rachel Beasley Chakrapani Kalyanaraman Brian M Suzuki Matthew P Jacobson Colette Dissous James H McKerrow David H Drewry William J Zuercher Rahul Singh Conor R Caffrey 2016-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0004356 https://doaj.org/article/1f31106f26284b5db634a718d8bb99bb EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4709140?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004356 https://doaj.org/article/1f31106f26284b5db634a718d8bb99bb PLoS Neglected Tropical Diseases, Vol 10, Iss 1, p e0004356 (2016) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2016 ftdoajarticles https://doi.org/10.1371/journal.pntd.0004356 2022-12-31T08:17:08Z 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 ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Polo ENVELOPE(28.967,28.967,65.600,65.600) PLOS Neglected Tropical Diseases 10 1 e0004356 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Thavy Long R Jeffrey Neitz Rachel Beasley Chakrapani Kalyanaraman Brian M Suzuki Matthew P Jacobson Colette Dissous James H McKerrow David H Drewry William J Zuercher Rahul Singh Conor R Caffrey Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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 ... |
format |
Article in Journal/Newspaper |
author |
Thavy Long R Jeffrey Neitz Rachel Beasley Chakrapani Kalyanaraman Brian M Suzuki Matthew P Jacobson Colette Dissous James H McKerrow David H Drewry William J Zuercher Rahul Singh Conor R Caffrey |
author_facet |
Thavy Long R Jeffrey Neitz Rachel Beasley Chakrapani Kalyanaraman Brian M Suzuki Matthew P Jacobson Colette Dissous James H McKerrow David H Drewry William J Zuercher Rahul Singh Conor R Caffrey |
author_sort |
Thavy Long |
title |
Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni. |
title_short |
Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni. |
title_full |
Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni. |
title_fullStr |
Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni. |
title_full_unstemmed |
Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni. |
title_sort |
structure-bioactivity relationship for benzimidazole thiophene inhibitors of polo-like kinase 1 (plk1), a potential drug target in schistosoma mansoni. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2016 |
url |
https://doi.org/10.1371/journal.pntd.0004356 https://doaj.org/article/1f31106f26284b5db634a718d8bb99bb |
long_lat |
ENVELOPE(28.967,28.967,65.600,65.600) |
geographic |
Arctic Polo |
geographic_facet |
Arctic Polo |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 10, Iss 1, p e0004356 (2016) |
op_relation |
http://europepmc.org/articles/PMC4709140?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004356 https://doaj.org/article/1f31106f26284b5db634a718d8bb99bb |
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https://doi.org/10.1371/journal.pntd.0004356 |
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PLOS Neglected Tropical Diseases |
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10 |
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e0004356 |
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