Abstract 3098: CETSA for navigating your chemistry and exploring the biology of protein degraders

Abstract Protein degradation is a non-classical modality with the potential to tackle therapeutically interesting proteins, previously deemed undruggable. In this area, CETSA is a powerful technology for identifying new binders, assessing target engagement, and investigating the mechanism of action of the degraders in the intact cell environment - without the need to modify your compound, the proteins or the cellular environment. CETSA can provide insights into the binding of the degrader to both the E3 ligase and the protein of interest (POI), as well as follow the downstream cellular and molecular effects. Here we will exemplify how CETSA can be applied in various stages of drug discovery to provide biologically relevant data to guide the design and optimization of new degraders. For example, CETSA can provide valuable information of the cell permeability and the in-cell performance of the degrader, which is important for understanding how the degrader enters cells and reaches its target proteins. By combining data from CETSA with data from degradation readout, in our case quantitative proteomics, it is possible to correlate cellular target engagement potencies with degradation efficiency and importantly, also identify any drug: protein binding that does not result in degradation By using the proteome-wide CETSA Explore format, the selectivity of the degrader and the downstream protein consequences of the elimination of the target protein could be studied. Citation Format: Victoria Brehmer, Stina Lundgren, Tomas Friman, Daniele Amadio, Alexey Chernobrovkin, Daniel Martinez Molina. CETSA for navigating your chemistry and exploring the biology of protein degraders abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3098.