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.

There is a rapidly growing number of successful applications of DNA-encoded libraries for the discovery of bioactive molecules in pharmaceutical development. Recently, the integration of DNA-encoded libraries with machine learning and computational methods has gained traction, aiming to predict the activity of commercially available compounds. This presentation will highlight ongoing developments and provide a meta-analysis of recent reports, identifying the current state of capabilities and limitations.

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.

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 discuss how we leverage the implementation of novel strategies and new modalities to enable our DELT platform having a sustainable impact on Roche's small-molecule discovery pipeline.

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.