Abstract 3163: Discovery of highly selective ligands for the Bcl-2 family of proteins using DNA-encoded chemical libraries

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. De Novo design and synthesis of non-traditional encoded libraries such as a reversible covalent compound library and beyond Lipinski’s rule of five (bRo5) macrocyclic (MC) libraries have significantly expanded the chemical space available for DEL screening, and further enhances the feasibility of discovering highly selective ligands for challenging oncology targets. We will present examples of affinity-based ligand discovery targeting protein-protein interactions within the Bcl-2 family of proteins, specifically focusing on MCL1 and BFL1. We highlight the multiplexed DEL selection strategy employed and elucidate the molecular details around the uniqueness of the ligand interactions. Citation Format: Ying Zhang, Sana Bazzaz, Corey Bienstock, Paolo A. Centrella, Marie-Aude Guié, John P. Guilinger, Anthony D. Keefe, Matthew A. Clark. Discovery of highly selective ligands for the Bcl-2 family of proteins using DNA-encoded chemical libraries [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 3163.