Activity-Based DNA-Encoded Library Screening

• Published in: ACS combinatorial science Vol. 21; no. 5; pp. 425 - 435
• Main Authors: Cochrane, Wesley G, Malone, Marie L, Dang, Vuong Q, Cavett, Valerie, Satz, Alexander L, Paegel, Brian M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.05.2019
• Subjects: Combinatorial Chemistry Techniques; DNA - chemistry; Drug Evaluation, Preclinical; Electrochemical Techniques; High-Throughput Screening Assays; Peptides - chemical synthesis; Photochemical Processes; Small Molecule Libraries - analysis; Solid-Phase Synthesis Techniques; DNA-encoded library; OBOC; droplet; drug discovery; microfluidics
• ISSN: 2156-8952; 2156-8944; 2156-8944
• DOI: 10.1021/acscombsci.9b00037

Robotic high-throughput compound screening (HTS) and, increasingly, DNA-encoded library (DEL) screening are driving bioactive chemical matter discovery in the postgenomic era. HTS enables activity-based investigation of highly complex targets using static compound libraries. Conversely, DEL grants efficient access to novel chemical diversity, although screening is limited to affinity-based selections. Here, we describe an integrated droplet-based microfluidic circuit that directly screens solid-phase DELs for activity. An example screen of a 67 100-member library for inhibitors of the phosphodiesterase autotaxin yielded 35 high-priority structures for nanomole-scale synthesis and validation (20 active), guiding candidate selection for synthesis at scale (5/5 compounds with IC50 values of 4–10 μM). We further compared activity-based hits with those of an analogous affinity-based DEL selection. This miniaturized screening platform paves the way toward applying DELs to more complex targets (signaling pathways, cellular response) and represents a distributable approach to small molecule discovery.