Biochem/physiol Actions

NAV-2729 (IC50 of 1.5 μM) has a therapeutic benefit in reducing the adverse effect of diabetic retinopathy in animal models.

Originally characterized as a non-nucleotide-competitive and reversible ARF6-selective inhibitor (IC50 = 1.4 μM without GEF and 2.4 μM with 100 nM ARNO or BRAG2/GEP100) that targets ARF6 GEF-binding region, NAV-2729 prevents GEF-dependent ARF1 & ARF6 activity (% inhibition of BRAG2Sec7PH-stimulated GTPase activity/[NAV-2729] = 50% Δ17Arf1/10 μM and 15% Δ13Arf6/25 μM) with higher potency against BRAG2- than ARNO-dependent ARF1 activity (64% vs. 20% Δ17Arf1 inhibition at 25 μM in the presence of respective GEF sec7 domain). NAV-2729 treatment effectively inhibits G-alpha-q downstream signaling pathways and anchorage-independent colony growth of Mel92.1 & Mel202 melanoma cells in vitro (10 μM) as well as uveal melanoma tumor establishment in Mel202 xenograft mice in vivo (30 mg/kg/day i.p.).