Drug Design Leads To Desired Enzyme Inhibitors

A research team at the Novartis Institutes for Biomedical Research, in Basel, Switzerland, has discovered the first potent non-bisphosphonate inhibitors of farnesyl pyrophosphate synthase (FPPS), an enzyme associated with osteoporosis and certain cancers (Nat. Chem. Biol., DOI: 10.1038/nchembio.421). Bisphosphonates are efficient at blocking FPPS activity and are popular drugs for treating osteoporosis and other bone diseases. For more than a decade, drug developers have longed to treat breast cancer and several infectious diseases by targeting FPPS with modified bisphosphonates. But the compounds’ high accumulation in bone cells hampers their ability to work elsewhere. In seeking a solution to this problem, Novartis’ Wolfgang Jahnke and colleagues turned to fragment-based drug design, a strategy that aims to create blockbuster drugs by identifying chunks of molecules or even mere functional groups that may bind only weakly to biological targets. The fragments are then expanded and optimized to make a drug lead with stronger affinity and promising pharmacokinetic characteristics. The non-bisphosphonate FPPS inhibitors that the Novartis team developed feature a benzyloxycarbonyl scaffold and allosterically block the enzyme by slipping into a previously unknown binding pocket.