Abstract 398: Systematic identification and translation of novel targeted protein degradation mechanisms

Abstract The rise of Targeted Protein Degradation (TPD) is rapidly changing perceptions about therapeutic target druggability and drug design. However, the majority of degraders in clinical and preclinical development rely on the recruitment of a single E3 ligase, Cereblon, highlighting a pressing need to identify and translate novel mechanisms. Moreover, the discovery of molecular glue degraders is hampered by the prevailing serendipitous nature of their discovery. To unlock the potential of this modality we have developed proprietary cell-based screening platforms, SITESEEKER® and GlueSEEKER™, to uncover novel TPD mechanisms. These technologies exploit vast libraries of computationally-derived coded peptide fragments within the context of a pooled degradation-based phenotypic screen. Specifically, SITESEEKER® screens have identified a cache of degrader mechanisms that rely on hijacking components of the UPS machinery. GlueSEEKER™ utilizes peptide libraries to create a diverse suite of surface-edited E3 ligases to systematically explore neo-substrate degradation across a variety of E3 ligases and Proteins-of-Interest (POI).PhoreMost is progressing a pipeline of monovalent and heterobifunctional oncology degrader programmes arising from its platforms. We describe a novel set of small molecule heterobifunctional degraders that operate via an E3 ligase distinct from Cereblon or VHL-based PROTACs. Mechanistically, these degraders function via a CUL1-SKP1 SCF complex FBOX substrate receptor and demonstrate potential for enhanced cancer-selective degradation of POIs. Finally, we uncover neomorphic interactions revealed by GlueSEEKER™ that provide translational insights for the degradation of both precedented and unprecedented substrates of the E3 ligase, Cereblon. Citation Format: Christian Dillon. Systematic identification and translation of novel targeted protein degradation mechanisms [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 398.