Some extracellular signals are transmitted via GPCRs (G protein coupled receptors) to intracellular G proteins controlling physiological processes that are frequently deregulated in cancer. G proteins are heterotrimers (Gαβγ) and several families have been described. Recently, non-receptor intracellular proteins that activate G proteins have been characterized, opening the way for their exploitation as pharmacological targets. GIV is a non-receptor protein that activates the alpha subunit Gαi3. The Gαi3-GIV interface is a promising anti-metastasis target because its disruption blunts the pro-metastatic behavior of cancer cells. In a joint effort led by Dr. Mikel García-Marcos at Boston University, we have mapped the binding site of GIV on Gαi3 and screened a library of small molecules that yielded two compounds that displace GIV from Gαi3. But the two molecules are not specific for Gαi3 and not cell permeable, preventing their use as therapeutic inhibitors of an intracellular target. We aim at studying the binding to Gαi3 of new compounds that specifically inhibit the interaction with GIV.
Docking model of a short GIV fragment (left), or the small organic molecule NF023 (right) bound to Gai3 protein, based on NMR measurements (bottom).