GOALI: Expanding the DNA-encoded Library (DEL) Toolbox to New Oxidative Transformations

About This Grant

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professors Jennifer Schomaker and Jeffrey Martell of the University of Wisconsin-Madison and Dr. Jing Chai at GSK are advancing DNA-encoded chemical library (DECL) technology to prepare and screen new compounds with potential bioactivity against diseases untreatable with known pharmaceuticals. DECLs are synthesized by tagging chemical precursors with small, unique fragments of DNA to ‘bar-coded’ the precursors. These are then reacted in a combinatorial fashion to generate millions-to-billions of novel chemical entities for testing against previously ‘undruggable’ proteins. While this strategy is low-cost and efficient, a major drawback is the inability of fragile DNA tags to tolerate oxidation conditions, which restricts the diversity of the resulting compound libraries. To address this challenge, the Schomaker and Martell teams are developing mild oxidative reactions that preserve the integrity of the DNA, significantly broadening the scope of drug candidates that are made with DECL technology. They are also investigating how altering the positioning of DNA barcodes influences library preparation and their resulting bioactivity. Drawing on their combined expertise, the team is designing innovative on-DNA oxidations catalyzed by Earth-abundant metals, such as copper. From a training perspective for young scientists, UW and GSK are creating a two-week summer course on the syntheses, analyses and applications of DECLs to encourage academic researchers to adapt their new synthetic methods to the preparation of novel drug libraries. The theory portion of the course surveys the benefits of DELC for drug discovery and highlights the challenges of conducting chemistry on DNA, while the hands-on portion focuses on the manipulation, synthesis and analyses of DNA-linked organic compounds. This proposal brings together expertise in reaction methodology (Schomaker), use of non-genomic DNA to construct hybrid catalysts to accelerate reactions (Martell), and capabilities in analytical chemistry, molecular biology and informatics (Chai, GSK) to advance the power of DNA-encoded chemical libraries (DECLs). Typical approaches to prepare large (> 1,000,000), unique compound libraries cost millions-to-billions of dollars ; however, DECL technology, which combines DNA barcoding with high-throughput chemistry, enables the creation and screening of billions of compounds at a fraction of the usual cost. A big challenge in expanding the scope of DECLs has been the lack of viable oxidative transformations that can be conducted on DNA, as DNA barcodes often degrade under oxidative conditions. This GOALI collaboration between GSK and UW-Madison is developing powerful oxidative methods for on-DNA library synthesis to expand the structural diversity and Fsp3 of current drug screening libraries. The goals of this collaboration are: 1) developing three-component oxidative cyclization reactions on DNA, 2) merging on-DNA Cu-mediated oxidation with three-component click reactions to expand DEL diversity, and 3) creating DNA-scaffolded catalysis for efficient oxidation reactions with minimal damage to DNA. Significance and broader impacts of this work stems from: 1) developing complexity-generating oxidative methods that are successfully conducted on DNA, 2) applying new methods to generate novel DELs that expand GSK’s bioactive/therapeutic chemical space, 3) providing new drug candidate leads with improved bioactivity, efficacy and ADMET properties to the broader community, and 4) validating methods for the analyses of DECL able to utilize shared instrumentation in academic settings. GSK and UW are establishing freely accessible protocols for the community by creating a two-week workshop on the theory and practical aspects of DNA-encoded library construction, analysis and screening to encourage other academic labs to adopt this technology. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.