At Forge Therapeutics, we are developing medicines targeting metal-dependent enzymes found in nature. Over 30% of known enzymes across all species are metalloenzymes covering all major enzymes classes: hydrolases, transferases, oxidoreductases, lyases, isomerases, and ligases. Metal ions, including zinc, magnesium, iron, calcium and manganese, are the essential ingredient in these metalloenzymes.
Metalloenzymes and disease
A substantial fraction of enzymes in nature require metals for their catalytic activity. These metalloenzymes are central to a wide variety of biological processes and because metalloenzymes are critical to nearly all biological pathways in all living organisms, they represent a rich target space for drug development. At Forge, we have ‘metallo-mined’ the human genome as well as bacterial, fungal, and viral genomes to create linkage maps between metalloenzymes and disease.
Metalloenzymes in Inflammatory Disease
A specific major shortcoming in the field of metalloenzyme drug development is the limited chemical space employed to bind the active site metal ion with an almost exclusive reliance on a small number of functional groups regardless of the metal ion and target. At Forge, we have industrialized a one-of-a-kind metalloenzyme drug discovery process to create an innovative drug discovery platform: BLACKSMITH. Distinct from traditional approaches for ‘hit’ discovery using high throughput screens with large libraries of compounds, the Forge approach starts with metal-ligand interactions to identify selective metal-binding fragment pharmacophores (MBPs) from a proprietary library of >500 MBPs. Intelligently selected fragments result in a greater and more effective chemical diversity to rapidly identify key interactions between a fragment and the metalloenzyme active site. Using bioinorganic and medicinal chemistry principles, these MBP fragments are transformed into therapeutic leads using a proprietary fragment growth merging strategy incorporating computational chemistry and structural biology.