Mutations in KRAS drive a series of oncogenic events, including tumor cell proliferation and invasion, resistance to apoptosis, and sustained angiogenesis. Farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT-1) are two enzymes involved in KRAS prenylation. FGTI-2734 is a potent RAS C-terminal mimetic dual FT and GGT-1 inhibitor with IC50 values of 250 and 520 nM, respectively. FTI-2148 inhibited the prenylation of HDJ2, RAP1A, KRAS, and NRAS in NRAS-transformed NIH3T3 cells as compared with DMSO-treated controls. In human pancreatic (MiaPaCa2) and lung (H460) cancer cells, FGTI-2734 at 3 - 30 µM increased the cytosolic accumulation of HRAS and RAP1A, and inhibited the membrane association of KRAS and NRAS. Treatment with FGTI-2734 at 30 µM prevented GFP-KRASG12V-CVIM localization to the membrane in human cancer cell lines including MiaPaCa2, H460, Calu6, A549, and DLD1 cells. In MiaPaCa2 cells, administration with FGTI-2734 at 30 μM inhibited the RAF-1 kinase activity. FGTI-2734 treatment at the doses of 1 - 30 µM suppressed HDJ2 farnesylation and RAP1A geranylgeranylation in MiaPaCa2, L3.6pl, Calu6, A549, H460, and DLD1 cells, and induced Caspase-3 and PARP cleavage only in MiaPaCa2, L3.6pl, and Calu6 cells lines. In mouse xenograft models, intraperitoneal administration of FGTI-2734 (100 mg/kg/day) inhibited the growth of KRAS-dependent MiaPaCa2 tumors but not the mutant KRAS-independent tumors[1].
作用机制
FGTI-2734 is a potent CAAX tetrapeptide mimetic dual inhibitor of FT and GGT-1 that inhibits the membrane localization of KRAS in multiple human cancer cell lines.
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