NE10790 is a FPP synthase inhibitor. It inhibited prenylation in J774 macrophages and osteoclasts. NE10790 selectively prevents Rab prenylation in intact cells, inhibited the activity of recombinant Rab GGTase in vitro, but did not affect the activity of recombinant FTase or GGTase I.
Prenylation (transfered from farnesyl diphosphate (FPP)) is essential for the function of the modified proteins. FPP, which is sequentially produced by condensation reaction involving FPP synthase, is product of the mevalonate pathway. NE10790, a phosphonocarboxylate analogue of the potent bisphosphonate risedronate, is a weak anti-resorptive agent. NE10790 partially inhibits (30–50%) FPP synthase activity in vitro. NE10790 dose-dependently reduced viable J774 cell number with an IC50 of ∼1.2 mM. In J774 cells in vitro, 1.5 mM NE10790 inhibited incorporation of [14C]mevalonic acid into bands of prenylated small GTPases of higher molecular mass only (22–26 kDa proteins; most likely Rab GTPases based on molecular mass). The effect of NE10790 was dose-dependent, with complete inhibition of incorporation of [14C]mevalonic acid into 22–26-kDa proteins at a concentration of 1 mM. Furthermore, in intact cells, NE10790 prevented geranylgeranylation of proteins that were substrates for Rab GGTase but did not affect prenylation of proteins that were substrates for GGTase I. Moreover, geranylgeranylation of Rab6 (a substrate for Rab GGTase) was completely inhibited by NE10790 (1.5 mM, 18 h) but was not affected by GGTI-298 in J774 cells demonstrating that NE10790 specifically prevented the prenylation of Rab6 but not Rap1 or Ha-Ras[1].
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