Abstract
Chemical genomics has been applied extensively to evaluate small molecules that modulate biological processes in Saccharomyces cerevisiae. Here, we use yeast as a surrogate system for studying compounds that are active against metazoan targets. Large-scale chemical-genetic profiling of thousands of synthetic and natural compounds from the Chinese National Compound Library identified those with high-confidence bioprocess target predictions. To discover compounds that have the potential to function like therapeutic agents with known targets, we also analyzed a reference library of approved drugs. Previously uncharacterized compounds with chemical-genetic profiles resembling existing drugs that modulate autophagy and Wnt/β-catenin signal transduction were further examined in mammalian cells, and new modulators with specific modes of action were validated. This analysis exploits yeast as a general platform for predicting compound bioactivity in mammalian cells.
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21 February 2020
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Acknowledgements
We are indebted to Jia-mi Han and Jin-yan Tao for technical assistance, and Dian-wen Ju, Kuninori Suzuki and Michael Costanzo for valuable discussions. MWW is supported by a Shanghai Municipality Science and Technology Development Fund (Grant number 18430711500). CB and YY are supported by a JSPS Grant-in-Aid for Scientific Research on Innovative Areas (17H06411). SCL was supported by a RIKEN Foreign Postdoctoral Research Fellowship. TX is supported by National Natural Science Foundation of China (Grant number 61571202).
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SCL, YY, MY, CLM, and CB designed chemical genomics studies; DHY and MWW designed HTS campaign and pharmacological experiments; JN and SS performed computational analysis (processing chemical-genetic profiles from raw sequencing data, data normalization, correlation analyses and plot generation); SCL, YY, MY, CLM, and CB interpreted computational results; FLZ, YZ, WJG, LJS, QL, JBX, TX, and YYF performed HTS and validation experiments; FLZ, SCL, YZ, DHY, JMY, YY, MY, CLM, CB, and MWW analyzed the data; SCL, FLZ, YZ, DHY, CB, and MWW wrote the paper.
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Zhou, Fl., Li, S.C., Zhu, Y. et al. Integrating yeast chemical genomics and mammalian cell pathway analysis. Acta Pharmacol Sin 40, 1245–1255 (2019). https://doi.org/10.1038/s41401-019-0231-y
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DOI: https://doi.org/10.1038/s41401-019-0231-y
