Abstract C132: Screening of Molecular Glue Degraders Using the DIANTHUS Technology Platform

Abstract Molecular glues represent a promising therapeutic modality by inducing targeted protein-protein interactions (PPIs) to modulate disease-relevant pathways. The DIANTHUS technology platform (Spectral shift, TRIC) enables the rational design and discovery of molecular glues through a synergistic combination of computational chemistry, structural biology, and AI-driven screening. By leveraging dynamic interface mapping and conformational ensemble analysis, DIANTHUS identifies small molecules that stabilize or create neomorphic interfaces between E3 ubiquitin ligases and pathological target proteins, thereby triggering selective degradation or functional modulation. Here, we demonstrate the application of DIANTHUS to develop molecular glues targeting previously "undruggable" oncoproteins. Using molecular dynamics and high-throughput DIANTHUS Technology, we optimized lead compounds that induce CRBN-or VHL-mediated degradation of target protein implicated in cancer. Notably, DIANTHUS-derived glue molecules exhibited sub-micromolar potency in cellular assays and high selectivity over off-target proteins. This approach expands the toolbox for proximity-induced pharmacology and opens avenues for tackling challenging PPIs. Citation Format: Xinru Tang, Qian Wang, Lili Chai, Tiejun Bing. Screening of Molecular Glue Degraders Using the DIANTHUS Technology Platform [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C132.