Lead Generation Strategies

PCSK9 regulates LDL cholesterol by promoting LDL-receptor degradation. We identified a novel, druggable pocket on the PCSK9 C-terminal domain, enabling the development of a entirely novel class of small molecule inhibitors that are based on initial fragment hits. These compounds act through a distinct mechanism that does not block the classical PCSK9-LDLR interaction. We will present the discovery, lead optimisation, and mechanistic insights underpinning this innovative approach to PCSK9 inhibition.

Fragment-based screening can accelerate drug discovery by identifying novel scaffolds, but this approach is limited by the small libraries used experimentally and the challenging optimization process. To expand the explored chemical space, we performed structure-based virtual screening of large fragment libraries to discover inhibitors of a DNA repair enzyme implicated in cancer and inflammation. Fragment hits were rapidly optimized into potent inhibitors with anti-inflammatory and anti-cancer effects in cells.

We highlight our progress in drug discovery targeting proteins for which well-diffracting crystals of the protein–ligand complex may be difficult to obtain. Instead, we rely on liquid-state NMR for structure determination of these complexes. Building on this, we aim to develop atomic-resolution NMR-based calorimetry to quantify both enthalpic and entropic contributions to binding. This strategy opens new avenues for truly quantitative, structure-guided drug design.

DNA-encoded libraries, in the setup of Encoded Self-Assembing Chemical (ESAC) libraries, featuring the stable self-assembly of two DNA-encoded sub-libraries of fragments, allow for the identification of pairs of simultaneously binding fragments. In a second step, the most efficient linkage of individual fragment pairs will be obtained by selections of a second, DNA-encoded library of linkers (Linker-DEL), displaying the respective fragment pair.

The talk highlights an integrated workflow for hit-to-lead generation, seamlessly merging in silico machine learning(ML)-guided molecule selection with high-throughput experimentation (HTE). By integrating parallel synthesis, automation, and novel synthetic methodologies, including a C–H functionalisation toolbox, we access desired chemical matter efficiently. This approach enhances the exploration of chemical space and accelerates the discovery of novel chemical entities within lead series.

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a phosphatase with diverse regulatory roles in T cell and myeloid cell function. Historically, phosphatases have been considered undruggable due to their highly positively charged and homologous active sites. Jnana’s chemoproteomics RAPID platform identified multiple allosteric pockets on PTPN22 and discovered lead-like small molecule binders through high-throughput screening (HTS), including an indolinone series that functions as an allosteric activator of PTPN22. This HTS campaign also uncovered several reducing-agent sensitive chemotypes that are ubiquitous in screening libraries, highlighting a cautionary tale for the medicinal chemistry community regarding potential pitfalls in early hit discovery.

Helicases are enzymes that play a vital role in DNA and RNA metabolism, making them attractive targets in drug discovery. However, tackling these targets can present a range of challenges for assays typically used in traditional high-throughput screening. This talk will discuss how affinity-screening approaches can be designed into a hit-finding campaign to provide a strategic advantage in identifying helicase inhibitors.

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.

Access to high-resolution structural data for protein–ligand complexes is a prerequisite for structure-based drug design. For proteins refractory to X-ray crystallography, high-throughput structure determination by electron cryo-microscopy (cryo-EM) has the potential to be transformational for drug discovery. The talk will describe a workflow, from protein production through to end-user-accessible high-resolution structural data, applied to a biologically important ion-channel target in complex with a chemically diverse range of ligands. The depth of structural data generated provides important insights into protein-ligand structure-function relationships and demonstrates the potential of the workflow to support iterative compound design cycles.

The DELT Platform at Roche enables efficient lead generation through multiplexed screening of DNA-encoded libraries, combining large chemical diversity with rapid hit identification. By integrating innovative library design, automated selection workflows, and advanced data analytics, DELT accelerates the discovery of high-quality starting points for drug development. This talk highlights the platform’s recent impact across therapeutic areas, showcasing its role in driving Roche’s small molecule discovery pipeline.

This presentation will highlight recent progress on the CoDEL technology development and case examples to apply the CoDEL for the covalent inhibitors identification and optimisation. Particularly, by integrating activity-based protein profile (ABPP) and CoDEL together, covalent inhibitors target other amino acids' residues beyond cysteine and are identified for a series of protein targets.

Arachadonic acid 15-lipoxygenase (ALOX15) belongs to the lipoxygenase family, and is mainly responsible for catalyzing the oxidation of various ω-6 and ω-3 polyunsaturated fatty acid (PUFA) substrates to produce a variety of lipid components, contributing to the pathophysiological processes of various immune and inflammatory diseases. The translational pharmacology of different chemical series as well as the power of DEL screening to identify binders and elaboration to degraders will be shared.