Heterotrimeric G_q 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_q family-specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of G_q oncoproteins, mutant G_q 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_q 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_q protein oncogenes as well as broaden our mechanistic understanding of G_q protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G_(q) proteins as targets in drug discovery efforts.