Blacksmiths of modern medicine
Throughout history blacksmiths were critically important because they provided a variety of essential tools including cooking utensils, nails, hinges, axes, and horseshoes. Blacksmiths molded these tools from raw metals. The name blacksmith comes from working with iron in a forge. Iron becomes black in a forge because of the oxides that are formed from heating the metal.
At Forge Therapeutics, we are developing medicines targeting metal-dependent enzymes found in nature. Over 30% of known enzymes are metalloenzymes covering all major enzymes classes: oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Metal ions, including magnesium, zinc, iron, manganese, calcium, and copper are the essential ingredient in these metalloenzymes. At Forge, we are the blacksmiths of modern medicine, providing the tools to address any metalloenzyme challenge.
A substantial fraction of enzymes in nature require metals for their catalytic activity. These metalloenzymes are central to a wide variety of biological processes including photosynthesis, DNA modification, protein homeostasis, antibiotic resistance, and many others. Because metalloenzymes are critical to nearly all biological processes in all living organisms, they represent a rich target space for drug development.
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. The pioneering work by our scientific founder Prof. Seth Cohen determined that there is a largely untapped chemical space not utilized by traditional medicinal chemists that display superior activity and selectivity. Over the past 15 years Prof. Cohen has demonstrated that incorporating fragment based drug discovery (FBDD) with a focused set of metal binding pharmacophores (MBPs) is well suited for screening and developing inhibitors of these targets.
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. We have performed over 50 metalloenzyme FBDD screens with library hit rates of >15% thereby providing multiple starting points to build potent selective inhibitors of metalloenzymes over a variety of therapeutic areas.