While screening DELs and proposing hits from the resultant data has proven to be a straightforward exercise, the poor conversion rate of NGS-identified hits to confirmed ligands off-DNA complicates the realization of value expected from the technology. Here we highlight our Bead-Assisted Ligand Isolation-Mass Spectrometry (BALI-MS) hit-optimization platform that enables us to efficiently interrogate features from the primary DEL screen, therefore leading to a greater percentage of viable drug leads.

Solid-phase DEL technology unlocks opportunities to screen libraries using activity-based assays, from simple enzyme-substrate reactions to more complicated coupled enzymes systems (e.g. in vitro translation) and cells. This talk will describe new technology that we’ve developed for conducting activity assays directly on beads that does not require water-in-oil compartmentalization or custom droplet sorting instrumentation.  

DNA-encoded chemical libraries (DECLs) have increasingly been recognized as a powerful and economic technical tool for hit identifications. To increase successful rates of DECL selections, it's critical to develop valuable DNA-compatible reactions for constructing pharmaceutically preferred chemical structures. Here we would like to recall recent developments of on-DNA chemistry for DECL synthesis in this area and to focus on continuous endeavors of synthetic methodology exploitation at HitGen.

In partnership with a leading technology expert, GenScript has developed this ready-to-use, commercially accessible GenDECL^TM kit. This kit is a promising new tool for fueling drug discovery efforts, consisting of a collection of 18 sub-libraries with over 400 million drug-like chemical compounds.

The ease of writing, reading, and copying DNA information underpins DNA encoded libraries, but the information we store in DNA can be used in myriad ways. For example, I will describe how we analyze damage and mutations in DNA as a way to assess the DNA damage inflicted during encoded library synthesis. This analysis can quantify the suitability of particular reactions for encoded library development.

eDESIGNER is an algorithm that comprehensively generates DNA encoded library designs, enumerates and profiles samples from each library, and evaluates them to select the libraries to be synthesized. This presentation will address the eDESIGNER concept and how we use it at Lilly to improve the chemical space coverage and compound chemical properties of our DNA encoded libraries.

DNA-Encoded Chemical Libraries (DECLs) have transformed modern screening against biological targets; however, chemical reactions to form DECLs must be compatible with DNA. Similarly, the ring-closing metathesis (RCM) reaction has been a staple of modern synthetic organic chemistry for ring formation owing to its wide functional group tolerance and substrate generality. We describe the development of robust conditions for performing the RCM reaction in the context of a DECL platform.

Drug discovery is now blessed with a wide range of high-throughput hit identification strategies that have been successfully validated in recent years, with particular success coming from DEL Screening. This talk will focus on LCC’s design of novel di/tri-functionalised, 3D-rich, stereodefined building blocks for DEL technologies which can be employed to generate libraries of drug-like compounds and how recent advances in synthetic methodologies can be utilised to access these valuable scaffolds.

DEL technology, started in the early 2000s with just a handful of mostly academic groups. including mine at ETH, has developed into a valuable resource for small molecule drug discovery over the last few years. This talk will highlight the most important success stories and their respective DEL design. I will also discuss opportunities for improvement in the DEL field and the promises and limitations of different DEL architectures.

DNA-encoded libraries enable the screening of billions of small molecules at a depth of chemical space not available with other affinity screening methods and small molecule libraries. The analysis of data is more complex, however, requiring specialized visualizations to view potential SAR and off-DNA synthesis of the small molecule warhead to confirm binding. In this presentation, we will review the discovery of two clinical candidates from ELT screens, one an inhibitor of soluble epoxide hydrolase (sEH) and the other an inhibitor of receptor-interacting serine/threonine-protein kinase 1 (RIPK1).

I will present 2 or 3 case studies of molecules discovered from the first successful screening of DNA-encoded library (DEL) inside a living cell: oocytes from the South-African clawed frog Xenopus Laevis. Cell-based DEL screening benefits include broader target space (no requirement for purified target protein) and lower attrition rates (screening under physiological relevant conditions). I will also show how we have developed multiplex screening inside the oocytes.

X-Chem Inc. operates a DNA-Encoded Chemistry platform and associated downstream services to support a wide range of customers in their search for novel chemical equity.  This talk will introduce the platform and its achievements with a range of examples of licensed projects including oncology, infectious disease and CNS applications.   Examples will demonstrate the downstream services we provide including methods to rapidly identify hits, hit-to-lead, structural biology enablement and medicinal chemistry.

DNA-Encoded library (DEL) technology is a screening platform used throughout the pharmaceutical industry to discover novel chemical matter. Despite pharmaceutical interest in small-molecules capable of irreversibly binding to their targets, DEL technology has failed to demonstrate the ability to produce and discover covalent hit molecules. We will share recent successful covalent DEL screening efforts against Bruton’s tyrosine kinase and SARS-CoV-2 main protease, including evidence of covalent interactions and potent enzymatic activity.