Abstract 6052: Systematic identification of novel targeted protein degradation mechanisms using SITESEEKER® technology

Abstract The rise of Targeted Protein Degradation (TPD) is rapidly changing perceptions about therapeutic target druggability and is rewriting many preconceived notions on drug design. However, the majority of monovalent molecular glue and heterobifunctional degraders in clinical and preclinical development rely predominantly on the recruitment of a single E3 ligase, Cereblon. Arising resistance, toxicities and restricted Protein-of-Interest scope may limit clinical potential, highlighting the need to uncover novel TPD mechanisms. To expand the potential of this modality, we have developed SITESEEKER®, a screening technology operating at substantially greater magnitude of complexity than extant target discovery platforms. SITESEEKER® utilizes computationally-derived encoded mini-protein fragments with huge shape diversity to systematically identify novel degrader mechanisms and define functionally-active binding sites on targets. SITSEEKER® allows for the discovery of targets that may be missed through traditional gene editing or knockdown approaches and can additionally provide valuable mechanistic insights that help to inform, unlock and truncate the path from target ID to drug discovery. We describe the identification of a cache of degrader motifs which showcase the breadth of proteome space yet to be explored within TPD. Moreover, we identify peptide motifs capable of driving degradation in a selective manner with potential to be translated into tissue- or cancer-selective degraders. The functional dependencies of prioritized degraders have been mapped to their cognate E3 ligase using combinatorial screening, giving rise to a number of E3 ligases with potential to be hijacked for TPD. PhoreMost is progressing a pipeline of monovalent and heterobifunctional oncology degrader programs arising from its platform. We demonstrate the effective hijacking of selected E3 ligases, identified by SITESEEKER®, through the discovery of high affinity small molecule binders and subsequent discovery of efficient heterobifunctional degraders against selected Proteins-of-Interest. Citation Format: Christian Dillon. Systematic identification of novel targeted protein degradation mechanisms using SITESEEKER® technology 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 6052.