DNA encoded focused library is a powerful technology for the hit to lead optimization of the specific therapeutic target. The integration between FBDD and DNA encoded libraries(DEL) could provide an efficient way to design the focused DEL based on the privileged fragments of corresponding targets identified by diverse screening methods. This lecture will disclose the detailed examples to integrate DEL with FBDD for reversible and covalent inhibitors discovery.

Encoded library technologies—mRNA display, DEL, SELEX—have become increasingly important components of the early-discovery toolkit as targets become more complex. These technologies operate via affinity selection to identify ligands, which may or may not be functional. Given that binding is a prelude to function, we are developing technology to interface affinity-selection output (binders) scalably with activity-based and cellular screening for these various modalities.

For a DNA-encoded library (DEL) compound to bind a protein, the linker attaching it to the DNA must be tolerated. Understanding linker effects is essential for DEL applications, particularly when combined with machine learning. This presentation assesses linkerability of protein-binders based on co-crystal structures and examines how linker placement influences DEL data.

G-protein-coupled receptors (GPCRs) have an extremely complex allosteric landscape. This complexity plays a key role in determining their multifaceted signaling outcomes. In order to properly exploit this complexity, new ligands are needed. DNA-encoded chemical libraries (DELs) have proven to be a valuable tool for discovery of such novel GPCR allosteric modulators that can both teach us about GPCR allostery and serve as powerful lead molecules for pain and overdose.

GPCRs present unique challenges to drug discovery due to their low expression, structural complexity, and limited stability. I will describe how Structure Therapeutics integrates reagent and tool compound generation with biophysical and biochemical characterization to enable DEL screening and identify novel small-molecule starting points for obesity-related GPCR targets.

The commonly used assay for DNA-encoded chemical libraries (DELs) is a simple affinity selection with an immobilized protein on a bead. We present alternative approaches for discovery to improve selection results using bromodomains as a test bed target group. These include proximity labeling approaches using enzyme fusion proteins to selectively label hit DEL members with an affinity purification tag. We also present the use of DNA-linked compounds as assay probes and their application in assaying conventional compound collections and one-bead-one-compound (OBOC) libraries in high throughput screening (HTS). Assays include enzymatic activities and ligand binding.

GSK applies DNA-encoded library technology to accelerate oligonucleotide discovery for challenging targets. High-throughput, rapid validation of molecular interactions remains a bottleneck. This talk explores the development of novel biophysical assays to predict downstream oligonucleotide function and liabilities. Drawing from recent case studies, these mechanistic insights are applied to triage compounds earlier in the discovery pipeline and improve confidence in hit follow-up and lead optimization.

The DELT platform is a central hit identification methodology at Roche. We utilize property-driven building block selection and innovative library design to generate attractive chemical starting points for drug discovery programs. In this talk, I will present the application of DEL technology to generate starting points for a Roche MAGL inhibitor program and the development of 2 hit series toward advanced MAGL inhibitors.

DNA encoded libraries are the engine powering Nurix’s small molecule and degrader pipelines for novel targets. Using machine learning technology, we trained a foundation model on our high-quality DEL data that successfully predicts DEL binders given only the target protein sequence. We are combining this proprietary technology with our DEL screening platform to unlock E3 ligases as a target class and enable the discovery of ligands for induced proximity applications like heterobifunctional and molecular glue degraders.

This talk will describe microfluidics-enabled cellular phenotypic DEL workflow—MicDrop. We will introduce cellular DEL screen in droplets, followed by results from a cellular protein degradation screen with a validation library, as well as another set of screens with a prospective library. Our results show the benefits of bead replicates and how this new paradigm of DEL screen can accelerate the field of molecular glue discovery for TPD and beyond.

Herein, we report the discovery of PLX-66140, a potent CDK2 cereblon-based degrader. Using Plexium’s picowell DEL screening platform, we identified multiple CDK2 degrader hits. Medicinal chemistry optimization resulted in the identification of a selective and orally bioavailable drug development candidate. Oral administration of PLX-66140 in tumor-bearing mice demonstrated robust target degradation and enhanced anti-tumor activity over ATP-competitive inhibitors in multiple CCNE1-amplified mouse xenograft models at well tolerated doses.