GGTI-2418 is a highly potent, competitive, and selective geranylgeranyltransferase I (GGTase I) inhibitor. GGTI-2418 inhibits GGTase I and FTase activities with IC50s of 9.5 nM and 53 μM, respectively. GGTI-2418 also increases p27(Kip1) and induces significant regression of breast tumors[1].
The ability of the GTPases to mediate these tumorigenic events requires their posttranslational modification with farnesyl and geranylgeranyl lipids. The enzymes responsible for these modifications is geranylgeranyltransferase I (GGTI), and inhibitors of GGTI have been developed as potential anticancer drugs. GGTI-2418 is a potent and selective peptidomimetic inhibitor of GGTI. In vitro, GGTI-2418 inhibits GGTI with IC50 of 9.5 ± 2.0 nM. And it demonstrates competitive inhibition of GGTase I against the H-Ras-CVLL protein with a Ki value of 4.4 ± 1.6 nM. Tumors from mice treated with 100 mg/kg GGTI-2418 intraperitoneally daily or 200 mg/kg every third day grew to only average tumor sizes of 139 ± 17 or 276 ± 26 mm3, respectively, corresponding to tumor growth inhibitions of 94% and 77%, respectively (P < 0.005 for both). These data clearly indicate that GGTI-2418 potently inhibits the growth of breast tumor xenografts with either daily or intermittent dosing. Moreover, in seven mice with a total of 17 tumors, treatment with 100 mg/kg GGTI-2418 resulted in tumor regression between 34 and 100%, with an average of 60% ± 4%[1].
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