(1245-B) CETSA®: Accelerating Primary Screening of P53 through Rapid High-Throughput Target Engagement Technology
Monday, February 5, 2024
2:00 PM – 3:00 PM EST
Location: Exhibit Halls AB
Abstract: Ensuring target engagement for potential drugs is crucial in drug discovery to avoid failures in later stages. Numerous projects encounter setbacks due to efficacy issues or the inability to demonstrate lead candidates interacting with the intended target in a complex cellular environment. The utility of using CETSA® technology to measure target engagement in intact cells is increasingly exploited in high throughput screening, examples demonstrate low false positive rates (Rowlands et al. 2023 PMID: 36736830). Here, using our newly developed high-throughput screening platform, the analysis of a high throughout plate based CETSA® for screen on the well-known transcription factor target p53 is demonstrated. Hits identified in this screen possess a unique advantage, binding to the target in a physiologically relevant cellular matrix and in a binding-mode agnostic manner from the outset. This departure from traditional methods emphasizes a rapid target-to-hit lead generation strategy, prioritizing compounds interacting with the endogenous target in living cells first, followed by analysis of hit material activity. This "shortcut" to identifying chemical matter active in living cells not only streamlines the drug discovery process but also offers substantial cost savings compared to traditional high-throughput screening approaches, that involve extensive assay development time on recombinantly produced proteins or modified cell lines, and still rely on target engagement assessment downstream. This assay cascade highlights a rapid target-to-hit lead generation strategy placing the emphasis on finding chemical matter that interacts with endogenous target in living cells first, followed by analysis of hit material activity. The ‘shortcut’ to chemical matter active in living cells represents significant potential cost savings in comparison to assay development time on recombinantly produced proteins and/or modified cell lines for traditional HTS screening approaches that still rely on target engagement assessment downstream.