Abstract 3091: Discovery of highly selective ligands with unique binding modes for challenging oncology targets using DNA-encoded chemical libraries

Abstract DNA-encoded chemical library (DEL) technology enables the efficient screening of large collections of encoded compounds and has emerged as a powerful tool for hit identification in recent years. The technology allows for the multiplexed interrogation of target-ligand binding interactions and results in DEL hits with unusual binding modes and desirable selectivity. This screening methodology is particularly effective for oncology targets. Examples of discovery of highly selective ligands for challenging oncology targets, including kinases, protein-protein interactions, and receptors, will be presented. We will illustrate how DEL campaign strategies directly aim at novel binding modes, and provide molecular details around the uniqueness of these interactions. Furthermore, we will show how these novel binding modes lead to unique pharmacology with direct benefit to patients. Lastly, we will demonstrate how X-Chem’s high-quality encoded libraries enhance the tractability and novelty of chemical equity discovered with the platform. Citation Format: Ying Zhang, Anthony Keefe, Matthew A. Clark. Discovery of highly selective ligands with unique binding modes for challenging oncology targets using DNA-encoded chemical libraries 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 3091.