Positioning High-Throughput CETSA In Early Drug Discovery Through Screening Against B-Raf And PARP1

A new study published ahead-of-print by SLAS Discoverydescribes an evaluation of microplate-based high-throughput cellular thermal shift assay (CETSA HT) performed at AstraZeneca to assess its suitability and reliability for application to early drug discovery campaigns.

The CETSA is a technology that measures intracellular compound target engagement by quantifying changes in the thermal stability of the target protein in live cells. The technology has a number of advantages over alternative methods including the ability to detect binding to the intended target in cellular models without requiring any overexpression or tagging of the target protein, or any chemical modifications or probe compounds.

Novel CETSA HT assays are described for two important oncology targets, B-Raf and PARP1, and applied to both primary screening for hit identification and SAR screening for lead optimization. Comparisons are performed with conventional drug discovery assay technologies including a biochemical probe-displacement binding assay and a cellular imaging assay.

The findings demonstrate that CETSA HT shows good correlations to other assay formats, but can also highlight different compound responses that allow for a more thorough understanding of cellular effects. CETSA HT can be reliably applied throughout various stages of early drug discovery to quantify intracellular binding to the desired target, providing a better understanding of the action of small molecules which may help advance novel therapeutic drugs.