Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi
- Department for International Development
- 1 January 2013
- Document Type:
- Journal Article
- Ioset, J.R., Chatelain, E., Keenan, M., Best, W.M., Diao, H. Charman, S.A., White, K.L., Ryan, E., Abbott, M.J., Alexander, P.W., Chaplin, J.H., von Geldern, T.W., Perez, C.J., Cornwall, S.M.J., Gong Chen, Keatley, S.K., Thompson, R.C.A., and Wang ZhiSen
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.
Keenan, M.; Alexander, P.W.; Chaplin, J.H.; Abbott, M.J.; Diao, H.; Wang ZhiSen; Best, W.M.; Perez, C.J.; Cornwall, S.M.J.; Keatley, S.K.; Thompson, R.C.A.; Charman, S.A.; White, K.L.; Ryan, E.; Gong Chen; Ioset, J.R.; von Geldern, T.W.; Chatelain, E. Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi. Future Medicinal Chemistry (2013) 5 (15) 1733-1752. [DOI: 10.4155/fmc.13.139]
Published: 1 January 2013
Document Type: Journal Article
Authors: Ioset, J.R. Chatelain, E. Keenan, M. Best, W.M. Diao, H. Charman, S.A. White, K.L. Ryan, E. Abbott, M.J. Alexander, P.W. Chaplin, J.H. von Geldern, T.W. Perez, C.J. Cornwall, S.M.J. Gong Chen Keatley, S.K. Thompson, R.C.A. Wang ZhiSen