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Positioning High-Throughput CETSA in Early Drug Discovery through Screening against B-Raf and PARP1

Joseph Shaw1, Ian Dale1, Paul Hemsley1

  • 11 Discovery Biology, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, UK.

SLAS Discovery : Advancing Life Sciences R & D
|December 14, 2018
PubMed

Insights

High-throughput Cellular Thermal Shift Assay (CETSA HT) measures drug target engagement in cells. This method for B-Raf and PARP1 shows good correlation with other screening technologies, supporting its use in drug discovery.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Drug Discovery

Background:

  • Cellular target engagement assays are crucial in early drug discovery.
  • Cellular Thermal Shift Assay (CETSA) measures target engagement by assessing protein thermal stability changes upon compound binding.
  • High-throughput CETSA (CETSA HT) enables broader application but has been limited to few targets.

Purpose of the Study:

  • To develop and validate novel high-throughput CETSA (CETSA HT) assays for B-Raf and PARP1.
  • To assess the correlation of CETSA HT with established drug discovery screening technologies.
  • To demonstrate the applicability of CETSA HT across hit identification and lead optimization stages.

Main Methods:

  • Development of two novel high-throughput CETSA (CETSA HT) assays.
  • Assays focused on B-Raf and PARP1 targets within their physiological cellular environment.
  • Comparative analysis of CETSA HT results with conventional cellular and biochemical assays.

Main Results:

  • Successful implementation of CETSA HT for B-Raf and PARP1 targets.
  • Demonstrated strong correlation between CETSA HT and other established screening technologies.
  • Validation of CETSA HT's utility throughout hit identification and lead optimization phases.

Conclusions:

  • CETSA HT is a valuable and broadly applicable methodology for drug discovery.
  • This technology effectively measures target engagement in a native cellular context.
  • CETSA HT supports the advancement of drug discovery campaigns toward target-engaging molecules.
Keywords:
B-RafCETSAPARP1target engagement

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