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

doi:10.4155/fmc.13.139

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

Centre for Drug Candidate Optimisation

Research output: Contribution to journal › Article › Research › peer-review

21 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 language	English
Pages (from-to)	1733 - 1752
Number of pages	20
Journal	Future Medicinal Chemistry
Volume	5
Issue number	15
DOIs	https://doi.org/10.4155/fmc.13.139
Publication status	Published - 2013

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Keenan, M., Alexander, P. W., Chaplin, J. H., Abbott, M. J., Diao, H., Wang, S. Z., Best, W. M., Perez, C., Cornwall, S. MJ., Keatley, S. K., Thompson, R. C. A., Charman, S. A., White, K. L., Ryan, E., Chen, G., Ioset, J. R., von Geldern, T. W., & 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

@article{0c38ed40cf1c4bdfbb502e08b5d194ca,

title = "Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi",

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.",

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

year = "2013",

doi = "10.4155/fmc.13.139",

language = "English",

volume = "5",

pages = "1733 -- 1752",

journal = "Future Medicinal Chemistry",

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publisher = "Future Science Ltd.",

number = "15",

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Keenan, M, Alexander, PW, Chaplin, JH, Abbott, MJ, Diao, H, Wang, SZ, Best, WM, Perez, C, Cornwall, SMJ, Keatley, SK, Thompson, RCA, Charman, SA, White, KL, Ryan, E, Chen, G, Ioset, JR, von Geldern, TW & Chatelain, E 2013, 'Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi', Future Medicinal Chemistry, vol. 5, no. 15, pp. 1733 - 1752. https://doi.org/10.4155/fmc.13.139

TY - JOUR

T1 - Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi

AU - Keenan, Martine

AU - Alexander, Paul W

AU - Chaplin, Jason Hugh

AU - Abbott, Michael J

AU - Diao, Hugo

AU - Wang, Sen Z

AU - Best, Wayne Morris

AU - Perez, Catherine

AU - Cornwall, Scott MJ

AU - Keatley, Sarah K

AU - Thompson, Richard Christopher Andrew

AU - Charman, Susan Ann

AU - White, Karen Louise

AU - Ryan, Eileen

AU - Chen, Gong

AU - Ioset, Jean Robert

AU - von Geldern, Thomas W

AU - Chatelain, Eric

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.future-science.com/doi/abs/10.4155/fmc.13.139

U2 - 10.4155/fmc.13.139

DO - 10.4155/fmc.13.139

M3 - Article

SN - 1756-8919

VL - 5

SP - 1733

EP - 1752

JO - Future Medicinal Chemistry

JF - Future Medicinal Chemistry

IS - 15

ER -

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

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