title: Lead identification to clinical candidate selection: drugs for Chagas disease.
abstract: Chagas disease affects 8 million people worldwide and remains a main cause of death due to heart failure in Latin America. The number of cases in the United States is now estimated to be 300,000, but there are currently no Food and Drug Administration (FDA)-approved drugs available for patients with Chagas disease. To fill this gap, we have established a public-private partnership between the University of California, San Francisco and the Genomics Institute of the Novartis Research Foundation (GNF) with the goal of delivering clinical candidates to treat Chagas disease. The discovery phase, based on the screening of more than 160,000 compounds from the GNF Academic Collaboration Library, led to the identification of new anti-Chagas scaffolds. Part of the screening campaign used and compared two screening methods, including a colorimetric-based assay using Trypanosoma cruzi expressing β-galactosidase and an image-based, high-content screening (HCS) assay using the CA-I/72 strain of T. cruzi. Comparing molecules tested in both assays, we found that ergosterol biosynthesis inhibitors had greater potency in the colorimetric assay than in the HCS assay. Both assays were used to inform structure-activity relationships for antiparasitic efficacy and pharmacokinetics. A new anti-T. cruzi scaffold derived from xanthine was identified, and we describe its development as lead series.
authors.affiliation: Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
authors.affiliation: Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Chen
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Supek
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA.
authors.forename: Vince
authors.initials: V
authors.lastname: Yeh
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, CA, USA Department of Pathology, University of California, San Francisco, CA, USA Five Prime Therapeutics, San Francisco, CA, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Kellar
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, CA, USA Department of Pathology, University of California, San Francisco, CA, USA.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
authors.forename: Clifford
authors.initials: C
authors.lastname: Bryant
authors.affiliation: Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gallardo-Godoy
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Molteni
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA Dart Neuroscience, San Diego, CA, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Roach
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Khare
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA.
authors.forename: Monique
authors.initials: M
authors.lastname: Stinson
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA California Institute for Biomedical Research (Calibr), San Diego, CA, USA.
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.affiliation: Innovation, Technology, and Alliances, University of California, San Francisco, CA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Robertson
authors.affiliation: Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
authors.affiliation: Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Arkin
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Glynne
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, CA, USA Department of Pathology, University of California, San Francisco, CA, USA Skaggs School of Pharmacy and Pharmaceutical Science, University of California, San Diego, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: McKerrow
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, CA, USA Department of Pathology, University of California, San Francisco, CA, USA Skaggs School of Pharmacy and Pharmaceutical Science, University of California, San Diego, CA, USA jairlage@gmail.com.
authors.forename: Jair L
authors.initials: JL
authors.lastname: Siqueira-Neto
mesh_terms: D000818:Animals; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy; D003124:Colorimetry / Q000379:methods; D004195:Disease Models, Animal; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D058069:Neglected Diseases / Q000188:drug therapy; D054852:Small Molecule Libraries; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D019820:Xanthine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D054852:Small Molecule Libraries; D014344:Trypanocidal Agents; D019820:Xanthine
keywords: Chagas disease; cell-based assays; drug discovery; high-content screening; high-throughput screening