The growing scope of chemistries for DNA-encoded chemical library (DECL) synthesis has intensified the need for quantitative methods for validating their compatibility with DNA. We have developed a comprehensive approach for the assessment of chemical fidelity (reaction yield and purity), encoding fidelity (ligation efficiency), and readability (DNA compatibility), revealing the fate of the DNA-tag during DECL chemistry from a single platform. I will describe its utility in screening on-DNA chemistries.

DNA-encoded libraries (DELs) are increasingly popular as a source of protein ligands. An important issue moving forward is to develop more structurally diverse and stereochemically complex DELs, particularly with respect to “largish” molecules, such as non-peptidic macrocycles that may be suitable for targeting difficult-to-drug proteins, such as transcription factors. Recent efforts along these lines will be described.

Inhibitors of Myc identified from DNA-encoded library screens of p300. Hits from a 2009 DEL affinity screen of p300 were incorporated into GSK’s HTS screening deck as part of routine compound collection enhancement. These compounds were identified in a phenotypic HTS for Myc inhibition which allowed for rapid target deconvolution and follow on DEL screens for additional chemical series.

This talk will introduce Reaction Biology’s KRAS Pathway Drug Discovery suite including the full spectrum of recombinant KRAS pathway proteins such as wild type and mutated KRAS, GEFs, GAP, and kinases as well as established biochemical and biophysical assays including the direct inhibition of mutated KRAS activities and RAS-SOS1 interactions. 

Although the evolution from initial fragment to advanced hit or lead is possible without routine crystallographic support, high-resolution structures of the protein–fragment complex greatly facilitate the process. However, it can be challenging to routinely obtain these crystals. In these instances, NMR spectroscopy is the method of choice to guide the medicinal chemistry campaign. I present case studies of recent NMR structure-based drug design for fragments.

Inhibition of TNFα and other cytokine signaling pathways such as IL-17, IL-23, and IL-6 have been clinically validated via macromolecular biologic drugs; however, efforts to modulate these pathways with small molecules by directly inhibiting interaction with their cognate receptors have been impeded by the challenges associated with the requirements of a small molecule to disrupt high-affinity, protein-protein interactions.  Here, we will present a fragment-based approach that was leveraged to develop orally efficacious TNFα inhibitors that function through an allosteric desymmetrization mechanism.

With the exponential growth in the development of targeted protein degraders comes significant challenges for the structural biology and computational modelling communities. Numerous examples now exist in the literature of the exquisite SAR possible through modifications of these molecules and this has driven a need to generate atomic level ternary complex information to assist degrader design and elucidate mechanism of action. Here we will present our approach combining biophysical and computational methods to generate weighted models to support medicinal chemistry campaigns.

Research of tomorrow is moving towards a more collaborative, open source and platform-independent environment. CDD Vault facilitates more effective research and collaboration by easing the chemical and biological complexity of drug discovery with chemical and batch registration, data visualization and an ELN integrated into a private, secure and collaboration vault. 

Increasingly diverse chemical matter arising from new therapeutic modalities require biophysical data to inform the often-complex structure-function relationship but such data is more challenging to acquire. Real-time label-free biosensing assays can help meet the growing need for identification and mechanistic characterization of diverse chemical matter. A variety of novel assays are presented with reference to example data from early discovery projects at Genentech.

Small-molecule drug discovery can be hindered by aggregating compounds that act as non-selective inhibitors of drug targets. These aggregates appear as false positives in high-throughput screening campaigns and can complicate structure-activity relationships during triage and compound optimization. They can also cause problems in secondary biophysics assays, such as SPR. I’ll discuss high-throughput microplate-based approaches to identify compound aggregation.

Confirmation of target engagement in relevant physiological environment ensures successful drug discovery and the right project prioritization. Welcome to learn about the CETSA methodology and principles for compound profiling including tool finding, primary screening, hit confirmation and generation of relevant structure-activity relationship (SAR) data.