Lead identification to clinical candidate selection: drugs for Chagas disease

R Jeffrey Neitz; Steven Chen; Frantisek Supek; Vince Yeh; Danielle Kellar; Jiri Gut; Clifford Bryant; Alejandra Gallardo-Godoy; Valentina Molteni; Steven L Roach; Shilpi Khare; Monique Stinson; Arnab K Chatterjee; Stephanie Robertson; Adam R Renslo; Michelle Arkin; Richard Glynne; James McKerrow; Jair L Siqueira-Neto

doi:10.1177/1087057114553103

Lead identification to clinical candidate selection: drugs for Chagas disease

J Biomol Screen. 2015 Jan;20(1):101-11. doi: 10.1177/1087057114553103. Epub 2014 Oct 3.

Authors

R Jeffrey Neitz¹, Steven Chen¹, Frantisek Supek², Vince Yeh², Danielle Kellar³, Jiri Gut⁴, Clifford Bryant¹, Alejandra Gallardo-Godoy¹, Valentina Molteni², Steven L Roach⁵, Shilpi Khare², Monique Stinson², Arnab K Chatterjee⁶, Stephanie Robertson⁷, Adam R Renslo¹, Michelle Arkin¹, Richard Glynne², James McKerrow⁸, Jair L Siqueira-Neto⁹

Affiliations

¹ Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
² Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA.
³ 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.
⁴ 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.
⁵ Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA Dart Neuroscience, San Diego, CA, USA.
⁶ Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA California Institute for Biomedical Research (Calibr), San Diego, CA, USA.
⁷ Innovation, Technology, and Alliances, University of California, San Francisco, CA, USA.
⁸ 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.
⁹ 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.

PMID: 25281737
DOI: 10.1177/1087057114553103

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.

Keywords: Chagas disease; cell-based assays; drug discovery; high-content screening; high-throughput screening.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Line
Chagas Disease / drug therapy
Colorimetry / methods
Disease Models, Animal
Drug Discovery / methods*
Drug Evaluation, Preclinical
High-Throughput Screening Assays*
Humans
Mice
Neglected Diseases / drug therapy
Small Molecule Libraries
Trypanocidal Agents / chemistry
Trypanocidal Agents / pharmacology*
Trypanosoma cruzi / drug effects*
Xanthine / chemistry
Xanthine / pharmacology

Substances

Small Molecule Libraries
Trypanocidal Agents
Xanthine

Grants and funding

R01 AI090605/AI/NIAID NIH HHS/United States