ARF6 (GTPase ADP-ribosylation factor 6) can be activated by a variety of different ARF-guanine nucleotide exchange factors (ARF-GEFs), depending on the stimulating factor or cell type and is an attractive candidate as an effector of Gαq signaling. NAV-2729 is allosteric, non-nucleotide-competitive and reversible ARF6-selective inhibitor with IC50 value of 1.5μM. NAV-2729 directly inhibited ARF6 as evidenced by nearly equipotent inhibitory effects toward spontaneous and ARF-GEF-catalyzed ARF6 nucleotide exchange. Treatment of Mel92.1 and Mel202 cells with NAV-2729 at concentration of 10μM inhibited ARF6 activation, as well as mimicked ARF6 and GEP100 knockdown by driving GNAQ from the cytoplasmic vesicles to the plasma membrane and reducing anchorage-independent colony growth. NAV-2729 also blocked all of the known downstream signaling pathways of oncogenic GNAQ, including PLC/PKC, Rho/Rac, YAP, and β-catenin. Administration of NAV-2729 at dose of 30mg/kg, i.p., daily, reduced uveal melanoma cell proliferation and tumorigenesis in a mouse model[2].
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