title: Discovery of ML358, a Selective Small Molecule Inhibitor of the SKN-1 Pathway Involved in Drug Detoxification and Resistance in Nematodes.
abstract: Nematodes parasitize ∼1/3 of humans worldwide, and effective treatment via administration of anthelmintics is threatened by growing resistance to current therapies. The nematode transcription factor SKN-1 is essential for development of embryos and upregulates the expression of genes that result in modification, conjugation, and export of xenobiotics, which can promote resistance. Distinct differences in regulation and DNA binding relative to mammalian Nrf2 make SKN-1 a promising and selective target for the development of anthelmintics with a novel mode of action that targets stress resistance and drug detoxification. We report 17 (ML358), a first in class small molecule inhibitor of the SKN-1 pathway. Compound 17 resulted from a vanillamine-derived hit identified by high throughput screening that was advanced through analog synthesis and structure-activity studies. Compound 17 is a potent (IC50 = 0.24 μM, Emax = 100%) and selective inhibitor of the SKN-1 pathway and sensitizes the model nematode C. elegans to oxidants and anthelmintics. Compound 17 is inactive against Nrf2, the homologous mammalian detoxification pathway, and is not toxic to C. elegans (LC50 > 64 μM) and Fa2N-4 immortalized human hepatocytes (LC50 > 5.0 μM). In addition, 17 exhibits good solubility, permeability, and chemical and metabolic stability in human and mouse liver microsomes. Therefore, 17 is a valuable probe to study regulation and function of SKN-1 in vivo. By selective targeting of the SKN-1 pathway, 17 could potentially lead to drug candidates that may be used as adjuvants to increase the efficacy and useful life of current anthelmintics.
authors.affiliation: †Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, United States.
authors.forename: Satyamaheshwar
authors.initials: S
authors.lastname: Peddibhotla
authors.affiliation: ⊥Department of Biology and Genetics Institute, University of Florida, Gainesville, Florida 32611, United States.
authors.forename: Pauline
authors.initials: P
authors.lastname: Fontaine
authors.affiliation: ⊥Department of Biology and Genetics Institute, University of Florida, Gainesville, Florida 32611, United States.
authors.forename: Chi K
authors.initials: CK
authors.lastname: Leung
authors.affiliation: †Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Maloney
authors.affiliation: †Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, United States.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hershberger
authors.affiliation: ⊥Department of Biology and Genetics Institute, University of Florida, Gainesville, Florida 32611, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: §Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United States.|∥Center for Natural Products, Drug Discovery and Development, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Bousquet
authors.affiliation: §Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United States.|∥Center for Natural Products, Drug Discovery and Development, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
authors.affiliation: †Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, United States.
authors.forename: Arianna
authors.initials: A
authors.lastname: Mangravita-Novo
authors.affiliation: ‡Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, United States.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.affiliation: †Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, United States.
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.affiliation: †Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, United States.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Malany
authors.affiliation: ⊥Department of Biology and Genetics Institute, University of Florida, Gainesville, Florida 32611, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Choe
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000737:chemistry* / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006373:Helminthiasis / Q000188:drug therapy / Q000469:parasitology; D006801:Humans; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000871:Anthelmintics; D029742:Caenorhabditis elegans Proteins; D054852:Small Molecule Libraries; D014157:Transcription Factors