title: Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, San Francisco, California, United States of America.|Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Thavy
authors.initials: T
authors.lastname: Long
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, San Francisco, California, United States of America.|Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.|Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
authors.affiliation: Department of Computer Science, San Francisco State University, San Francisco, California, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Beasley
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Kalyanaraman
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, San Francisco, California, United States of America.|Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Suzuki
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.affiliation: Center of Infection and Immunity of Lille, Université Lille Nord de France, Inserm U1019, CNRS-UMR 8204, Institut Pasteur de Lille, Lille, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Dissous
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, San Francisco, California, United States of America.|Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.affiliation: Department of Chemical Biology, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: David H
authors.initials: DH
authors.lastname: Drewry
authors.affiliation: Department of Chemical Biology, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Zuercher
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, San Francisco, California, United States of America.|Department of Computer Science, San Francisco State University, San Francisco, California, United States of America.
authors.forename: Rahul
authors.initials: R
authors.lastname: Singh
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, San Francisco, California, United States of America.|Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
mesh_terms: D000255:Adenosine Triphosphate; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008647:Mesocricetus; D015394:Molecular Structure; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012550:Schistosoma mansoni / Q000187:drug effects / Q000201:enzymology*; D012556:Schistosomicides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
chemical_list: D000255:Adenosine Triphosphate; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012556:Schistosomicides; D000097869:Polo-Like Kinase 1