Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi

Martine Keenan, Paul W Alexander, Jason Hugh Chaplin, Michael J Abbott, Hugo Diao, Sen Z Wang, Wayne Morris Best, Catherine Perez, Scott MJ Cornwall, Sarah K Keatley, Richard Christopher Andrew Thompson, Susan Ann Charman, Karen Louise White, Eileen Ryan, Gong Chen, Jean Robert Ioset, Thomas W von Geldern, Eric Chatelain

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

Background: Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. Results: We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. Conclusion: High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.
Original languageEnglish
Pages (from-to)1733 - 1752
Number of pages20
JournalFuture Medicinal Chemistry
Volume5
Issue number15
DOIs
Publication statusPublished - 2013

Cite this

Keenan, M., Alexander, P. W., Chaplin, J. H., Abbott, M. J., Diao, H., Wang, S. Z., ... Chatelain, E. (2013). Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi. Future Medicinal Chemistry, 5(15), 1733 - 1752. https://doi.org/10.4155/fmc.13.139