RAS is the most frequently mutated oncogene in cancer, with KRAS G12C mutations most commonly found in lung adenocarcinoma and colorectal cancer. Covalent inhibitors of KRASG12C have shown antitumour activity against advanced/metastatic KRAS G12C-mutated cancers. Here we report the identification of a new class of pyrazole-based KRASG12C inhibitors discovered by structure-based de novo design, the hit-to-lead, and lead optimisation leading to the discovery of JDQ443 and beyond.

The glycine to cysteine mutation at codon 12 of KRAS represents an Achilles' heel that has now rendered this important GTPase druggable. Herein we report our structure-based drug design approach that led to the identification of AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumours, including treatment of CNS metastases. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

The investigational agent RMC-9805 is an orally bioavailable, RAS(ON)G12D mutant-selective covalent inhibitor that forms a tri-complex between cyclophilin A and the “ON” state of RASG12D, enabling selective covalent engagement of Asp-12 and disruption of RAS signaling. RMC-9805 employs a warhead with low intrinsic reactivity and relies on a neomorphic protein interface to help catalyse the covalent reaction. RMC-9805 exhibits anti-tumour activity across a panel of human RASG12D cancer preclinical models.

Macrocyclic peptides have been attracting attention as a scaffold of protein-protein interaction inhibitors; however, limited success has been reported as an oral drug. Here, we report a methodology for creating a cell-permeable and orally bioavailable peptide drug by identifying important factors for better drug-likeness and developing library technologies affording highly N-alkylated cyclic peptides. As an example, the discovery of a RAS inhibitory clinical compound (LUNA18) will be presented.

Type I molecular glues from nature, FK506, Cyclosporin, and Rapamycin, have resulted in marketed therapies. The complex structures of these molecules have limited application to only a few protein targets. The presentation will describe the construction of large DEL and array libraries of type I molecular glues used for finding chemical starting points for a wide range of intracellular targets. Concepts of topological diversity, of optimization studies for cell permeability and of molecular glue characterization will be described.

We are building a bioinformatics and data integration platform to enable the discovery of effectors for molecular glue projects (e.g., E3 ligases for undruggable targets). This talk will offer an overview of our internal capabilities and systems, as well as external collaborations. It will feature an example to showcase the practical application of these elements, offering insights into our approach.

Our initial efforts to obtain a novel and well-balanced γ-secretase modulator with the potential to become an oral disease-modifier for early AD will be presented.

Mutations in the lysosomal protein GCase have been linked to increased risk for Parkinson’s Disease. Therapeutics aimed at enhancing GCase protein stability, trafficking, and activity are therefore of high relevance. Fragment screening by X-ray crystallography and other biophysical methods enabled the identification of new potentially druggable sites on the GCase protein surface. Compound elaboration produced high-affinity molecules able to positively modulate GCase activity in cells.

Diseases of the central nervous system, including neurodegenerative, neurological, and cancer-related diseases account for hundreds of millions of patients worldwide with poor or no treatment options. Furthermore, the validation of new therapeutic concepts in these areas suffers from a lack of potent and selective chemical tools. This talk will introduce work the Farnaby Lab is conducting, within the Dundee Centre for Targeted Protein Degradation, to understand how we can increase our ability to identify CNS active small molecule degraders.

I present discovery of VH3739937, an HIV-1 maturation inhibitor (MI) in clinical trials. HIV-1 maturation inhibitors (MIs) bind to the viral Gag polyprotein, preventing the final HIV-1 protease-mediated cleavage of Gag from occurring. VH3739937 is an MI with nanomolar activity vs. viruses with substitutions and deletions, conferring a much reduced sensitivity to previous MIs. In a Phase I study in healthy volunteers, VH-937 was found to be safe and demonstrated pharmacokinetic properties supporting QW dosing in an ongoing Phase II study in infected subjects.

The ability of macrocycles to adopt disc- and sphere-like conformations allows them to modulate difficult-to-drug targets. Consequently, macrocyclic drugs frequently reside in the beyond-rule-of-5 space where solubility, cell permeability, metabolic stability, and thereby oral bioavailability is challenging. Physics-based models provide mechanistic insight into cell permeability, (e.g., into molecular chameleonicity), while models developed by machine learning allow accurate differentiation of macrocycles that have high or low cell permeability.

Macrocyclic peptides can achieve passive permeability and oral bioavailability on par with small molecules. However, unlike small molecules, they are able to bind shallow, protein-protein interaction (PPI) interfaces with exquisite potency and and selectivity, opening up a new swath of targets and mechanisms-of-action inside and outside the cell. This presentation will showcase examples of successful intracellular PPI inhibitors derived from the Unnatural Products platform.