In 2018 we published in Nature our discovery of KAT6A inhibitor WM-1119, with the ensuing KAT druggability validation thereby oxygenating an industry of KAT drug discovery. Widely unknown is that WM-1119 discovery was challenged early on by noisy and misleading sets of hits, PAINS, and otherwise nuisance compounds. Here we chronicle this rollercoaster journey and impart what we hope are useful lessons to others at the public-private compound library design and drug discovery interface.

Efficient processes and high-quality chemical matter at every step of early drug discovery are critical to generate cost-effective, efficacious preclinical candidates. At Abbvie, the HTS team implements optimal target-based biochemical and cellular screens, followed by hit triage processes to eliminate false positives and advance hits to lead optimization and beyond. This talk will focus on best practices and strategies for generation of leads through robust assays, counter screens, orthogonal assays, novel technologies, and streamlined workflows.

As the drug-discovery industry focuses on increasingly difficult-to-drug targets, unlocking these through covalent modification can have a transformative effect on our perception of druggability. For targets without a well-defined binding site, an electrophile-first approach may be required to deliver tractable starting points where reversible hit finding had failed. This talk will focus on current best practice for covalent hit-identification at AstraZeneca, covering: screening platforms, library design, and hit validation.

The polar chemistry of activity-based protein profiling (ABPP) probes was reversed by deploying the nucleophilic hydrazine pharmacophore found in old CNS drugs to show organohydrazines are active-site-directed and mechanism-based inhibitors of protein classes that are difficult to drug. Using the first N-nucleophile fragment/probe library, we showed that potent and selective inhibitors can be developed and that reverse-polarity ABPP can advance small molecules that modulate diverse electrophile-dependent functions.

Astex has pioneered the application of structure-based approaches in drug discovery. I present a case study where crystal engineering was used to trap a therapeutic target protein kinase in distinct conformational states and deliver novel soakable crystal systems. This allowed the characterization of binding modes and mechanism-of-action of covalent and non-covalent compounds currently in the clinic. The combined results identified strategies to dial-out off-target effects and improve ligand selectivity.

^{The development of proximity-induced degraders into viable drug candidates still poses several challenges, including their relatively low cell permeability aswell as high degree of conformational flexibility due to the presence of flexible linker elements. I will present our strategy to identify conformationally constrained macrocyclic degraders. I will further delineate our lead generation approach, including ternary complex stabilization as well as property-based optimizations to ultimately achieve target degradation in vitro and in vivo.}

Murine in vivo studies have shown that PLD2 deficiency significantly reduced psoriasiform inflammation in IL-23-injected ears. Efficient and PLD2-selective hits from a high-throughput screen were identified and modified to improve potency and pharmacokinetic attributes. Structural features from hits identified in a DNA-encoded library screen were studied using in silico modeling and incorporated to improve binding kinetics. These efforts culminated in the identification of efficient in vivo active PLD2 inhibitors.

I provide updates on activity-based DEL technology, which interfaces solid-phase “OBOC” libraries with HTS-style activity assay. Our recent efforts focus on three thematic areas: 1) the discovery of translation modulators as a general strategy for interrogating the proteome via one universal biochemical activity assay, 2) development of pharmacokinetic assays for analyzing “beyond Rule of 5” libraries, and 3) novel 3D tissue culture strategies to enable cell-based DEL screening.

I discuss how credentialed ASMS platforms impact membrane protein, transcription factor, and cytokine PPI space. Examples will include rapid ID of series with SAR in Sanofi’s collection for a small G protein, and screening of a 400k library to generate a dozen attractive chemical scaffolds with potent inhibition of a peptide transporter. In case studies I will cover rationale for matching various modalities/workflows with early discovery-stage scenarios. 

RAPID is a next-generation chemoproteomics technology for identifying small molecules that bind reversibly to a pre-specified target of interest in a living cell. We will introduce the RAPID assay technology and describe its application towards the discovery of first-in-class inhibitors of SLC6A19, a genetically validated target for the treatment of PKU, as well as the first described ligands for the transcription factor IRF3 for the treatment of interferon-driven autoimmune disease.

I will present our platform to discover molecular glues that can bridge a productive interaction between an E3 ubiquitin ligase and a neosubstrate of interest to achieve targeted protein degradation. Using genetically engineered circuits, the platform relies on intracellular drug selection, bypassing many bottlenecks that exist with canonical in-vitro screening assays. This presents a novel approach to discover functional molecular glues from a first pass screen.

The design of small molecules that modulate the activity of disease-relevant proteins represents a longstanding challenge of medicinal chemistry. I will describe an approach for encoding this challenge into a microbial host and using it to guide the discovery and biosynthesis of targeted, biologically active molecules. Our high-throughput method accesses novel chemical fragments with functionalities uniquely suited to find new functional binding sites. I will discuss the case of PTP1B.