After nearly 30 years of development, DNA-encoded library (DEL) technology has matured significantly and is now a widely practiced method for small molecule drug discovery. Compared to traditional small molecule screening methods, DEL technology is dramatically lower in cost and offers marked improvements in efficiency and capacity for exploring vast chemical space. Initial hits to a target protein can be identified rapidly with minimal material input. DELs have become an essential tool in drug discovery, profoundly impacting the field.
The advancement of DEL technology can be divided into three major stages. The first stage, from 1992 to 2006, was the proof-of-concept period. During this time, researchers transitioned DEL technology from theory to practice. Pioneering demonstrations by the Neri, Harbury, and Liu groups promised an exciting future where molecular biology could be harnessed for small molecule discovery. New synthetic methods suitable for on-DNA chemical synthesis were developed, and systems were designed to program chemical synthesis using DNA sequences, enabling the in vitro evolution of wholly synthetic molecular populations.
The second stage, from 2006 to 2012, saw DEL technology move into real-world applications in drug discovery and initial adoption by the pharmaceutical industry. This period was marked by GSK’s acquisition of the DEL-based startup Praecis in 2006. The advent of next-generation DNA sequencing (NGS) during this era made the analysis of large libraries feasible for DELs prepared by DNA ligation-based tagging. This period included the landmark discovery of small molecules targeting Aurora A and p38 MAP kinase by the Praecis/GSK team. However, literature reports of DEL discoveries during this time were sparse and mostly from academic groups.
The third stage, from 2012 to the present, marks a period of rapid development and broad acceptance of DEL technology. New synthetic methods suitable for DEL synthesis have become abundant, and DEL chemistry has matured dramatically, yielding greatly improved libraries in terms of drug-likeness. DELs have nearly become a commodity and are commercially available from several providers at reasonable prices. DEL-based discovery is now practiced by all major pharmaceutical companies, with many published examples of discovery applications for biological targets with high therapeutic interest and DEL-discovered clinical candidates. Researchers are now expanding DEL use beyond the standard, in vitro selection for protein binders and into new application areas. Indeed, the future looks bright for DELs in drug discovery.
Unlike prior books on DEL technology, this book does not explain the basic principles and operation methods of DEL technology. Instead, it aims to describe recent major applications and progress in the field. We invited academic and industrial experts to review and demonstrate new applications of DEL technology, including machine learning using DEL data, one-bead-one-compound DELs for traditional biochemical screens, live cell-based DEL selections, DELs with covalent warheads, molecule optimization using focused DELs, and specific DEL applications for protein degraders. We hope this book inspires readers to think about new frontiers in the application of DELs to further promote the use of DEL technology in drug discovery.
https://orcid.org/0000-0003-2964-3520
