Abstract 407: Development of an integrated multi-modal platform for comprehensive analysis of targeted protein degraders in a drug discovery setting

With growth in the area of targeted protein degradation (TPD), there has been increasing interest in the development of analytical platforms which can facilitate efficient drug discovery processes. We provide a fully developed high throughput analytical platform to study and optimize protein degrader candidates in a comprehensive manner. Our platform consists of multiple orthogonal technologies that generate major mechanistic information and help advance TPD drugs rapidly through the preclinical development stages. Our platform is based on a well-defined degrader development strategy using advanced technologies and automated processes. Major analytical features include: • Binding and binary complex formation: assessment of warheads. Monitoring target protein binding interactions in both cell free and cellular systems, using surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and NanoBRET, respectively. • Ternary complex formation evaluation: assessment of degrader-induced protein-protein interactions in both cell free and cell-based systems, using homogeneous time-resolved fluorescence (HTRF) and NanoBRET respectively. • Cellular degradation profiling via a variety of methods, including automated capillary Western blotting, HiBiT and High Content Screening, enabling precise quantification of degradation kinetics and efficacy. • Proteome-wide specificity assessment using mass spectrometry. In our integrated data processing pipeline, we correlate physicochemical properties with degradation efficiency, to support SAR analysis and enhance the rational optimization of degraders. The platform has been proven to work across multiple E3 ligase systems, including CRBN, VHL and other tissue-specific ligases, thus supporting a wide range of TPD programs. Comparative case studies from several client-based programs exemplify the versatility of our platform and its capability to generate comprehensive data for effective decision making. Notably, we achieved high concordance between orthogonal methods. Modular design of the platform enables its segmentation to fit the needs of the clients’ individual specifications whilst retaining standardized work procedures for effective delivery of the project. This comprehensive analytical strategy addresses the challenges of TPD drug discovery and provides the scalability and reliability required for contract research organizations supporting multiple concurrent programs. Citation Format: Magdalena Kieltyka, Maciej Olszewski, Marta Smejda, Kamila Zaremba, Katarzyna Nosek, Magdalena Malik, Katarzyna Szafran. Development of an integrated multi-modal platform for comprehensive analysis of targeted protein degraders in a drug discovery setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 407.