Heterotrimeric G Proteins As Therapeutic Targets?

Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein-coupled receptors (GPCRs) to intracellular effectors. GPCRs are the largest family of membrane proteins encoded in the human genome and are the targets of about one-third of prescription medicines. However, to date, no single therapeutic agent exerts its effects via perturbing heterotrimeric G protein function, despite a plethora of evidence linking G protein malfunction to human disease. Several recent studies have brought to light that the G family-specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of G oncoproteins, mutant G variants that mostly exist in the active state. These data not only raise the hope that researchers working in drug discovery may be able to potentially strike G oncoproteins from the list of undruggable targets, but also raise questions as to how FR achieves its therapeutic effect. Here, we place emphasis on these recent studies and explain why they expand our pharmacological armamentarium for targeting G protein oncogenes as well as broaden our mechanistic understanding of G protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G proteins as targets in drug discovery efforts.