Identifying allosteric inhibitors of prenyl pyrophosphate synthases in a multistage structure-based screening approach

The mevalonate pathway is responsible for the production of all isoprenoids in mammalian cells. Downstream metabolites include cholesterol, dolichol, and ubiquinone. Consequently, this pathway is crucial to a plethora of biological processes, for example, in maintaining the integrity of cell membranes and the balance of reproductive hormones. Additionally, isoprenoids are essential for the post-translational modification and in turn the membrane targeting of small GTPases, signalling proteins that play a central role in cell survival and proliferation. As such, the mevalonate pathway is an attractive point of pharmacological intervention. The two enzymes farnesyl pyrophosphate (FPP) synthase and geranylgeranyl pyrophosphate (GGPP) synthase are of particular interest as potential anticancer targets. In a multistage screening approach employing X-ray crystallography, we have identified novel inhibitors of FPP synthase that bind to a new druggable pocket adjacent to the enzyme’s active site. The ongoing optimization process has recently achieved submicromolar in vitro potency. Interestingly, our drug discovery effort has also led to surprising insights into a fundamental property of FPP synthase. Based on this success, we have started work implementing the same structure-based approach to find GGPP synthase inhibitors. The progress on this front will also be discussed.