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High Content Screening of Small Molecule Modulators Targeting Heat Shock Response Pathway

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Heat Shock Proteins and Stress

Part of the book series: Heat Shock Proteins ((HESP,volume 15))

Abstract

Phenotypic high content screening (HCS) has resurged in recent years as an important platform in the drug discovery paradigm, particularly to address the serious challenges in the current target based approaches. Using the highly conserved heat shock response (HSR) pathway as a therapeutic intervention point, we established a cell based, high throughput, multiplexing, and disease relevant phenotypic screening platform for small molecule HSF1 modulators in cancer and neurodegenerative diseases. In this chapter, the authors reviewed their systematic design of methodology and workflow in detail, including the characterization of cellular phenotypic changes, image analysis and quantification, assay development and automation, screening operation and quality control, counter-screen and lead optimization, target identification and mechanism of action study. Selected compounds from the phenotypic screening, including novel HSF1 activators and HSF1 inhibitors, were discussed in regard to their chemical structures, therapeutic effects, and cytotoxicity for potential drug development. The authors also addressed the uncertainties and risks in target deconvolution, which still remains to be the most difficult hurdle in phenotypic screening. Recent HCS advances in tissues, organs and whole organisms, such as 3D tissue imaging, organ-on-a chip, IPS derived cell models, relevant animal models, etc., may bring an effective solution for delivering target-specific, first-in-class drugs in the future.

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Acknowledgements

The authors would like to thank all the supports received from everyone at Alpine Therapeutics, Inc. Special acknowledgements are given to Dr. Dorothy Wang for her critical review of the manuscript.

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Authors and Affiliations

  1. Department of Biology, Alpine Therapeutics, Inc., San Diego, CA, 92129, USA

    Daniel Zhang & Bin Zhang

  2. Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Daniel Zhang

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  1. Daniel Zhang
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Editors and Affiliations

  1. College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer, Houston, TX, USA

    Punit Kaur

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Zhang, D., Zhang, B. (2018). High Content Screening of Small Molecule Modulators Targeting Heat Shock Response Pathway. In: Asea, A., Kaur, P. (eds) Heat Shock Proteins and Stress. Heat Shock Proteins, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-90725-3_8

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