Discovering Protein-Protein Interaction Modulators from DNA-Encoded Chemical Library Screens
Sept. 23, 12:10 pm. Degraders and Molecular Glues Track

Paige Dickson, Senior Principle Scientist

DNA-encoded chemical library (DEL) technology enables the identification of new ligands which engage a desired biomolecular target, supporting an essential step of any early drug discovery program. Because DEL screening is an affinity-selection technique, the utilization of multiple parallel screening conditions is straightforward and enables putative mechanistic classification of enriched library compounds. Screen design drives the ability to identify ligands with specific mechanisms of action, including competitive inhibitors, agonists, and protein-protein interaction inhibitors and stabilizers. Here, we will describe the process of designing a selection to inform desired PPI mechanisms of action, and the application of this technology to two case studies including a stabilizer of the eIF2B/(p)eIF2a complex.

Chemomics of DEL: Building Protein Structure–Function Maps and Machine Learning Models from Untapped Screening Data
Sept. 23, 2:20 pm. AI/ML Enabled Drug Discovery Track

Erin Davis, CTO

DNA-Encoded Library (DEL) screens yield chemistry data at the -omics level, yet the vast majority is unused. X-Chem transforms this hidden knowledge into high-resolution protein structure–function maps and well-validated AI/ML models. By integrating advanced DEL analytics with computational and medicinal chemistry expertise, we produce SAR and predictive models across multiple modes of action, compressing years of discovery into a single experiment. This talk will demonstrate how moving beyond top hits to leverage the full dataset accelerates preclinical programs, uncovers novel chemical space, and redefines what is possible in small-molecule discovery.

POSTER
Advancing Macrocyclic DNA-Encoded Libraries for Challenging Targets

Ying (Ali) Chou, Senior Research Scientist

Macrocyclic DNA-encoded libraries (DELs) offer a powerful approach for discovering novel therapeutics, especially against challenging biological targets. Previously, we identified potent, selective macrocyclic inhibitors of Bcl-2 family proteins, optimized to low-nanomolar potency with favorable drug-like properties. Building on this success, our next-generation macrocyclic DEL features diverse ring sizes, rich stereochemistry, and proprietary chemistries, enabling efficient exploration of complex targets and accelerating the path to high-quality leads.

POSTER
Exploration, Exploitation and Summarization: Leveraging Thompson Sampling, Deep Data Mining and Pharmacophore Modeling to Access the Wealth of DEL Data for Drug Design Acceleration

RJ Swett, Director, Computational Chemistry

DNA-encoded library (DEL) screening has historically been used to identify hits from libraries of hundreds of billions of diverse molecules. We have developed novel methods to access and leverage the DEL screens into actionable SAR. Thompson sampling is method that has been re-implemented in our hands to harvest DEL data, both positive and negative. We have also developed novel pharmacophore methods that summarize the salient features of thousands of chemically and mechanistically related DEL compounds to allow for their broader use in Med Chem design. The combined access between the two methods produces data that facilitates not just hit identification, but into datasets that facilitate rapid acceleration of Medicinal Chemistry efforts.