Abstract 7027: Mass spectrometry-based proteomics for accelerating PROTAC and molecular glue drug discovery

Abstract Targeted protein degradation (TPD) platforms, including PROTACs and molecular glues, have revolutionized drug discovery as transformative therapeutic strategies. Recent advancements in mass spectrometry-based proteomics have dramatically improved assay speed and sensitivity, providing actionable insights into degradation profiles and drug efficacy on timescales compatible with discovery chemistry. This study evaluates the practical utility of advanced proteomic assays in supporting TPD research, focusing on their role in streamlining drug discovery pipelines. State-of-the-art proteomic workflows were employed to quantify the proteome-wide effects of PROTACs and molecular glues across diverse cellular models. Assay sensitivity, reproducibility, and throughput were rigorously assessed to determine their real-world applicability. Our findings reveal that these enhanced technologies generate robust, high-resolution datasets, capturing the dynamic interplay between target degradation, protein interactions, and cellular responses. This enabled the rapid identification of optimal degrader candidates and informed structure-activity relationship (SAR) studies. Mass spectrometry-based proteomics has emerged as an essential tool for advancing TPD strategies. By combining heightened sensitivity with operational feasibility, these assays offer critical insights that accelerate the development of PROTACs and molecular glues, bridging the gap between foundational research and clinical application. Citation Format: Michael J. Ford, Ravi Amunugama, David L. Allen, Richard C. Jones. Mass spectrometry-based proteomics for accelerating PROTAC and molecular glue drug discovery [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 7027.