Transformative high-throughput SPR-based fragment screening over large target panels can now be completed in days rather than years, enabling rapid, cost-effective ligandability testing and general pocket finding. Unlike conventional single-target fragment screens, this new approach reveals fragment hit selectivity and allows affinity cluster mapping across many targets. This helps identify selective fragments driven by favorable enthalpic contributions which possess more development potential towards favorable drug-like leads.

Fragment-based drug discovery is an efficient and powerful method for the development of lead compounds against important protein targets. However, there are only a small number of methods capable of registering low affinity fragment-protein interactions and all have significant limitations. We present here a new approach that leverages avidity effects to stabilize these weak interactions, allowing protein-binding fragments to be isolated from large libraries of low molecular weight compounds quickly and efficiently using only modest amounts of protein.

We describe the fragment-based discovery process behind a novel series of pan-RAS inhibitors, binding in the Switch I/II pocket. Through structure-enabled design, we develop these into a series of macrocyclic analogues, which effect inhibition of the RAS/RAF interaction and downstream phosphorylation of ERK. We will discuss some of the learnings gleaned from running a fragment screen against a target of this kind, and how best to follow up such hits.

A fragment based screening and design program leading to the discovery of pyrazolocarboxamides as novel inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment evolution, robust crystallography, and structure based design were used to afford advanced pyrazolocarboxamides with excellent biochemical and whole blood activity and improved kinase selectivity enabling investigation of RIP2 inhibition as a viable modality for the treatment of in?ammatory indications.

Werner Syndrome helicase (WRN) targets mismatch repair deficiency in cancer cells, making it a key target for MSI-H or MMRd tumors. In this presentation, we will describe the identification of a novel allosteric binding pocket using fragment-based screening. Moreover, we will discuss in more detail the chemical progression of one of the fragments hit and underscore the challenges faced in targeting this dynamic helicase.

Optimization of a fragment hit yields ABBV-973, a potent, pan-allele small molecule STING agonist for intravenous administration. Abstract is pending approval by AbbVie.

Recent chemoproteomics advances have enabled covalent ligand discovery across a broad range of new targets.  Here, we discuss the expanding role of chemical biology and chemoproteomics to support covalent lead discovery efforts, from early hit-finding to late lead optimization. I will include some case studies against cancer targets.

Chemical probes offer a valuable way to interrogate the function and disease-relevance of proteins and can also serve as leads for drug development, yet most proteins in the human proteome lack small-molecule ligands that can serve as probes. More generally, the boundaries, if any, on the ligandability, and therefore potential druggability, across proteomes remains poorly understood. I will describe our efforts to develop powerful photoaffinity-based chemical proteomic strategies to broadly map ligandable sites on proteins directly in cells, and how this information can be advanced into useful chemical probes for targets that play critical roles in human health and disease.

Belharra Therapeutics applies a novel chemistry-enabled non-covalent probe library and quantitative mass spectrometry to identify chemical probes that selectively bind any pocket, on any protein, in live cells. This next-gen chemoproteomics discovery engine identifies chemical probes that selectively engage diverse protein classes including transcription factors, adaptors, ion channels, and transporters, dramatically increasing the scope of the druggable proteome.

The design of covalent drugs targeting residues other than Cys,  such as His, or Tyr, is gaining significant traction. I will discuss strategies and opportunities to design covalent ligands targeting those residues  using both ligand-first structure-based design or covalent-fragment screening. I will present our successful implementations of both approaches.

We introduce COOKIE-Pro (COvalent Occupancy KInetic Enrichment via Proteomics), a novel method for quantifying covalent inhibitor binding kinetics proteome-wide. The method accurately determines kinact and KI values using a desthiobiotin probe and mass spectrometry. By integrating direct-to-biology synthesis with COOKIE-Pro, we enabled rapid screening of covalent fragments without purification, generating high-confidence hits within days. This approach overcomes limitations of traditional methods and accelerates development of selective covalent therapeutics.