Abstract 5331: DNA-encoded macrocyclic compound libraries for challenging targets

Abstract Increasingly drug discovery programs require the development of orally available and cell permeable classes of drugs derived from the chemical space beyond Lipinski’s rule of 5 (bRO5). The chameleon-like physicochemical properties and differentiated binding modes of bRO5 compounds make them suitable starting points, especially for difficult-to-drug targets beyond traditional small molecule drug discovery. The synthesis of macrocyclic (MC) peptide DNA-Encoded Libraries (DEL) aligns with these efforts and has been an important addition to the rapidly growing field of DNA-encoded small molecule library screening. DEL screening of de novo designed bRO5 compounds will aid the exploration of bRO5 chemical space. X-Chem’s macrocyclic compound libraries apply chemistries beyond traditional peptide formation and extend to the inclusion of diverse building block classes. A case study of a successful screening campaign utilizing these MC DEL for Bcl2 will be presented. Citation Format: Ying Zhang, Anthony Keefe, Paolo Centrella, John Cuozzo, Holly Soutter, Daniel Resnicow, Sevan Habeshian, Matt Clark. DNA-encoded macrocyclic compound libraries for challenging targets. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5331.