IGGi-11 is a first-in-class small molecule inhibitor of GIV-dependent G-protein cell signaling, binds to G-protein α-subunits (Gαi, Gαi3 ITC Kd=4 uM), specifically disrupts their engagement with GIV/Girdin.
IGGi-11 did not interfere with canonical G-protein signaling mechanisms triggered by GPCRs.
IGGi-11 also blocked GIV binding to Gαi3 in FP assays with an inhibition constant (Ki) of ~14 μM, and similar activity for the other two Gα proteins of Gi family: Gαi1 and Gαi2.
IGGi-11 also inhibited the ability of GIV to promote the steady-state GTPase activity of Gαi3, which reports increased nucleotide exchange in vitro. IGGi-11 does not affect GIV-independent aspects of G-protein regulation and function.
GIV/Girdin has emerged as a prototypical non-GPCR activator of G proteins that promotes cancer metastasis.
IGGi-11 has low membrane permeability because IGGi-11 contains two negatively charged carboxylate groups, and pro-drug IGGi-11me could be used for cellular function assays.