Grant: Project Grant

The human enzyme geranylgeranyl pyrophosphate synthase (hGGPPS) is responsible for the biosynthesis of the metabolite geranylgeranyl pyrophosphate (GGPP), which plays an important role in activating proteins involved in cancer progression. Recent biochemical studies have indicated that hGGPPS plays a leading role in the physiology of cancers that are resistant to most of the current chemotherapeutic drugs. A landmark trial in Multiple Myeloma (MM) showed improved overall survival in patients treated with the drug zoledronic acid, which blocks the production of the natural starting material required by hGGPPS to produce its metabolite GGPP. At the present time, clinically validated drugs that bind to hGGPPS are not available and consequently, the potential clinical value of this target is still unclear. There are very few exploratory compounds reported that inhibit hGGPPS, however, none of these molecules have yet been shown to have the appropriate biopharmaceutical properties to be useful in investigating the role of this enzyme in the progression of cancer. Therefore, the goal of our research is to develop inhibitors of hGGPPS that have good biopharmaceutical properties and consequently, can be used to properly validate this enzyme as a therapeutic target. We designed compounds with superior pharmaceutical properties to those previously reported in the literature that inhibit hGGPPS and induce cell-death to MM and other types of cancer cells without causing toxicity to healthy bone marrow and other healthy cells.