Inhibitors of
isoprenoid biosynthesis are widely used to treat human disease including
statins and nitrogenous
bisphosphonates. Due to the importance of core human
isoprenoid biosynthesis for diverse cellular processes related to
cancer cell growth and
metastasis, inhibition of this pathway may produce beneficial anticancer consequences. For example, ras oncogenes are well known;
ras proteins are overexpressed in many human
cancers, and these
proteins must be isoprenylated to function. The rho
proteins are important for regulating cell motility, and also must be isoprenylated. This has drawn significant attention to inhibitors of
protein prenyl transferases. In addition to the reactions that are targeted in current clinical applications, there are other
enzymes that have not been studied as extensively. Inhibition of these
enzymes, from
mevalonate kinase to
geranylgeranyl diphosphate synthase, could be attractive as a single agent
therapy or in combination with current agents for treatment of
cancers in which isoprenylated
proteins have been implicated. While detailed in vivo data for many of these putative targets is lacking, there have been several breakthroughs in recent years that could facilitate further studies. In particular, compounds that specifically inhibit some of the downstream
isoprenoid biosynthesis
enzymes have been developed and their effects in
cancer models are emerging. This review will discuss current knowledge of these lesser known
isoprenoid pathway
enzymes, identify trends in the development of their small molecule inhibitors, and describe the applications and effects of these compounds in
cancer models.